Haemorrhagic Diathesis. Thrombocytopenias and thrombocytopathias. Hemophylia. Haemorrhagic vasculitis. Etiology, pathogenesis. Clinical pattern. Treatment. The role of a doctor-dentist in treatment. Prophylaxis. Defence of Case History

Haemorrhagic Diathesis

Haemorrhagic diathesis is the disease characterized by the tendency to bleeding and repeated haemorrhages; they may occur spontaneously and may be caused by injuries; injury can be quite insignificant, which other­wise would never provoke bleeding in a normal individual.

Aetiology and pathogenesis. These are quite varied. Some types of haemorrhagic diathesis are hereditary but many of them can be caused by some external factors

Avitaminosis (deficit of vitamins C and P) is an especially predisposing factor. Some infections (long-standing sepsis, louse-born typhus, virus haemorrhagic fevers, icterohaemorrhagic leptospirosis), allergic condi­tions, some diseases of the liver, kidneys, and of the blood system can also provoke the onset of haemorrhagic diathesis.

Haemorrhagic diathesis can be classified by the pathogenesis into two major groups: (1) haemorrhagic diathesis due to disordered capillary permeability (haemorrhagic vasculitis, vitamin C deficiency, some infec­tious diseases, trophic disorders, etc.); (2) haemorrhagic diathesis due to disorders in the blood coagulation and anticoagulation system. The latter group is further subdivided into the following conditions:

A.     Haemorrhagic diathesis caused by disordered blood coagulation system:

(1)  first phase: congenital deficit of plasma components of thrombo-platelet formation (factors VIII, IX, XI), haemophilias A, B, C, etc.; deficit of thrombocyte components (thrombocytopathy, e.g. throm­bocytopenic purpura; see below);

(2)  second phase: deficit of plasma component of thrombin forma­tion—factors II, V, X, the presence of antagonists to them and of their inhibitors;

(3)  third phase: deficit of plasma components of fibrin formation-factors I (fibrinogen) and XII.

B.     Haemorrhagic diathesis caused by accelerated fibrinolysis (due to in­ creased synthesis of plasmin and insufficient synthesis of antiplasmin).

C.      Haemorrhagic diathesis caused by disseminated intravascular coagulation (thrombohaemorrhagic syndrome or coagulopathy of consumption) in which all procoagulants are utilized during massive intravascular coagulation and the fibrinolysis system is activated.

This concise classification of haemorrhagic diathesis is only conventional because several pathogenic factors are often involved. This classification covers a very large group of diseases, both hereditary and acquired, and also secondary syndromes arising against the background of the main disease (metastasizing malignant tumour, burn disease, etc.)

Primary haemostasis

Primary haemostasis is initiated when platelets adhere, using a specific platelet collagen receptor glycoprotein Ia/IIa, to collagen fibers in the vascular endothelium. This adhesion is mediated by von Willebrand factor (vWF), which forms links between the platelet glycoprotein Ib/IX/V and collagen fibrils.

The platelets are then activated and release the contents of their granules into the plasma, in turn activating other platelets and white blood cells. The platelets undergo a change in their shape which exposes a phospholipid surface for those coagulation factors that require it. Fibrinogen links adjacent platelets by forming links via the glycoprotein IIb/IIIa. In addition, thrombin activates platelets.

Secondary haemostasis

The coagulation cascade of secondary hemostasis has two pathways, the Contact Activation pathway (formerly known as the Intrinsic Pathway) and the Tissue Factor pathway (formerly known as the Extrinsic pathway) that lead to fibrin formation. It was previously thought that the coagulation cascade consisted of two pathways of equal importance joined to a common pathway. It is now known that the primary pathway for the initiation of blood coagulation is the Tissue Factor pathway. The pathways are a series of reactions, in which a zymogen (inactive enzyme precursor) of a serine protease and its glycoprotein co-factor are activated to become active components that then catalyze the next reaction in the cascade, ultimately resulting in cross-linked fibrin. Coagulation factors are generally indicated by Roman numerals, with a lowercase a appended to indicate an active form.

The coagulation factors are serine proteases (enzymes) except FVIII and FV which are glycoproteins. The serine proteases act by cleaving other proteins at specific sites. Factor XIII is a transglutaminase. Protein C is also a serine protease. The coagulation factors circulate as inactive zymogens.

Testing of coagulation

Numerous tests are used to assess the function of the coagulation system:

The contact factor pathway is initiated by activation of the "contact factors" of plasma, and can be measured by the activated partial thromboplastin time (aPTT) test.

The Tissue factor pathway is initiated by release of "tissue factor" (a specific cellular lipoprotein), and can be measured by the prothrombin time (PT) test. This is reported as an INR value when used for the dosing of oral anticoagulants such as warfarin.

The quantatative and qualitative screening of fibrinogen is measured by the thrombin time (TCT). Measurement of the exact amount of fibrinogen present in the blood is generally done using the Clauss method for fibrinogen testing. Many analysers are capable of measuring a "derived fibrinogen" level from the graph of the Prothrombin time clot.

If a coagulation factor is part of the contact or tissue factor pathway, a deficiency of that factor will affect only one of the tests: thus hemophilia A, a deficiency of factor VIII, which is part of the contact factor pathway, results in an abnormally prolonged aPTT test but a normal PT test. The exceptions are prothrombin, fibrinogen and some variants of FX which can only be detected by either aPTT or PT.

Deficiencies of fibrinogen (quantitative or qualitative) will affect all screening tests.

Definition of the “hemorrhagic syndrome“ and “hemorrhagic diathesis.”

Bleeding from a platelet disorder is usually localized to superficial sites such as the skin and mucous membranes, comes on immediately after trauma or surgery, and is readily controlled by local measures. In contrast, bleeding from secondary hemostatic or plasma coagulation defects occurs hours or days after injury and is unaffected by local therapy. Such bleeding most often occurs in deep subcutaneous tissues, muscles, joints, or body cavities. A careful and thorough history may establish the presence of a hemostatic disorder and guide initial laboratory testing.

 

Modern classification of hemorrhagic diathesis.Etiology, pathogenesis of hemorrhagic diathesis in the patients with disorders of coagulation, platelet and vessel wall.

Patients with platelet or vessel wall disorders usually bleed into superficial sites such as the skin, mucous membranes, or genitourinary or gastrointestinal tract. Bleeding begins immediately after trauma and either responds to simple measures such as pressure and packing or requires systemic therapy with glucocorticoids, desmopressin [1-desamino-8-D-arginine vasopressin (DDAVP)], plasma fractions, or platelet concentrates. The most common platelet/vessel wall disorders are (1) various forms of thrombocytopenia, (2) von Willebrand's disease (vWD), and (3) drug-induced platelet dysfunction.

Disorders of hemostasis

Clinical picture. The general clinico-morphological symptoms of haemorrhagic diathesis are haemorrhages into various organs and tissues, external and internal haemorrhages (from the gastro-intestinal tract, lungs, uterus, kidneys, etc.) and secondary anaemization. The disease is com­plicated by dysfunction of the haemorrhage-affected organs, by hemiparesis in disordered cerebral circulation, regional paralysis and paresis in compression of large nervous trunks by haematomas, haemar-throsis in repeated haemorrhages into the joints, etc.

Despite the great variety of haemorrhagic diatheses and certain diagnostic difficulties, accurate diagnosis is quite important for efficacious therapy in each particular case. The aetiological and pathogenetic factors of the disease should be properly considered for an^accurate diagnosis.

 

 

Petechia

 

Ecchymoses

 

 

PLATELET DISORDERS

Haemorrhagic diathesmis the subject of special study of senior medical students. Here we shall only acquaint the reader in general with thrombocytopenic purpura (Werlhof's disease).

 

 

Megacariocite

 

The prophylaxis of hereditary (familial) haemorrhagic diathesis in­cludes medico-genetic studies that may give the wife and husband the necessary information and advice concerning possible complications in their offspring; if haemorrhagic diathesis is not hereditary but acquired, measures should be taken to preclude development of diseases that may promote the onset of haemorrhagic diathesis.

 

Platelets arise from the fragmentation of megakaryocytes, which are very large, polyploid bone marrow cells produced by the process of endomitosis. They undergo from three to five cycles of chromosomal duplication without cytoplasmic division. After leaving the marrow space, about one-third of the platelets are sequestered in the spleen, while the other two-thirds circulate for 7 to 10 days. Normally, only a small fraction of the platelet mass is consumed in the process of hemostasis, so most platelets circulate until they become senescent and are removed by phagocytic cells. The normal blood platelet count is 150,000 to 450,000/ul. A decrease in platelet count stimulates an increase in the number, size, and ploidy of megakaryocytes, releasing additional platelets into the circulation. This process is regulated by thrombopoietin (TPO) binding to its megakaryocyte receptor, a proto-oncogene c-mpl. TPO (c-mpl ligand) is secreted continuously at a low level and binds tightly to circulating platelets. A reduction in platelet count increases the level of free TPO and thereby stimulates megakaryocyte and platelet production.

The platelet count varies during the menstrual cycle, rising following ovulation and falling at the onset of menses. It is also influenced by the patient's nutritional state and can be decreased in severe iron, folic acid, or vitamin B12 deficiency. Platelets are acute-phase reactants, and patients with systemic inflammation, tumors, bleeding, and mild iron deficiency may have an increased platelet count, a benign condition called secondary or reactive thrombocytosis. The cytokines interleukin (IL)-3, IL-6, and IL-11 may stimulate platelet production in acute inflammation. In contrast, the increase in platelet count that is characteristic of the myeloproliferative disorders such as polycythemia vera, chronic myelogenous leukemia, myeloid metaplasia, and essential thrombocytosis can cause either severe bleeding or thrombosis. In these patients, unregulated platelet production is secondary to a clonal stem cell abnormality affecting all the bone marrow progenitors.

Platelet Disorders

Autoimmune thrombocytopenias

Immune thrombocytopenic purpura

Immune thrombocytopenic purpura (ITP) is one of the most common autoimmune disorders. It occurs in 2 distinct clinical types, an acute self-limiting form observed almost exclusively in children (5 cases per 100,000 persons), and a chronic form, observed mostly in adults (3-5 cases per 100,000 persons) and rarely in children.

This disease is caused by autoantibodies to platelets. The antigenic target in most patients appears to be the platelet glycoprotein IIb/IIIa complex. Platelets with antibodies on their surface are trapped in the spleen, where they are efficiently removed by splenic macrophages. The mechanism of origin of these antibodies is not known. These antibodies may be directed towards the viral antigens and then cross-react with platelet antigens. They persist because of the failure of immune surveillance mechanisms to repress these antibodies. These antibodies can also react with the developing megakaryocytes in bone marrow, leading to decreased protection of platelets (ineffective thrombopoiesis).

ITP occurs commonly in otherwise healthy individuals and only rarely as the initial manifestation of lupus and other autoimmune disorders. HIV infection is often associated with immune thrombocytopenia in both adults and children.

Acute ITP

This is a disease that occurs exclusively in children. It affects both sexes equally and has a peak incidence in children aged 3-5 years. Most patients have a history of antecedent acute viral syndrome.

Onset is sudden, with symptoms and signs depending on the platelet count. Bleeding is usually mild unless the platelet count drops below 20,000/L. With platelet counts from 20,000-50,000/L, petechiae and ecchymoses are observed following mild trauma. With platelet counts below 10,000/L, generalized petechiae, ecchymoses, and mucosal bleeding occur. With platelet counts below 2000/L, widespread ecchymoses, hemorrhagic bullae, and retinal hemorrhage occur.

Physical examination reveals only the presence of petechiae and ecchymoses. The presence of lymphadenopathy or splenomegaly suggests other secondary causes of thrombocytopenia rather than ITP.

The peripheral smear shows a decreased number of platelets. Often, the smear shows giant platelets, which is a reflection of increased thrombopoietin-induced stimulation of the bone marrow. At times, the smear may show eosinophilia and lymphocytosis, possibly reflecting hypersensitivity to the inciting viral antigens. The bone marrow shows an increase in the number of megakaryocytes and signs of thrombopoietin-induced megakaryocyte stimulation (increase in number and ploidy, decrease in cytoplasm) resulting in large platelets in the periphery.

Thrombocytopenia in an otherwise healthy child with normal white and red blood cell counts almost always results from ITP. Findings from a careful history and physical examination help exclude other causes of thrombocytopenia, such as lupus and HIV infection. Acute leukemia is unlikely to manifest as an isolated thrombocytopenia without any abnormalities in the smear. Bone marrow examination is necessary only if atypical features (other abnormalities in the smear, sternal tenderness, lymphadenopathy, splenomegaly) or an unusual clinical course is evident.

Chronic ITP

This is typically observed in adults aged 20-40 years. It has an insidious onset, and a history of an antecedent infection need not be present. Unlike childhood ITP, chronic ITP is more common in females than in males. As in childhood ITP, the bleeding manifestations depend on the platelet count.

The diagnosis of ITP is established by the exclusion of other causes of thrombocythemia. The peripheral blood film should be examined to rule out thrombotic thrombocytopenic purpura (TTP) (fragments) or spurious thrombocytopenia resulting from clumping. Often, the smear shows giant platelets, which is a reflection of the increased thrombopoietin-induced stimulation of bone marrow. Bone marrow examination, which is not always necessary, shows increased megakaryocytes.

Alloimmune thrombocytopenia

Posttransfusion purpura

Posttransfusion purpura typically occurs 10 days following a transfusion. This syndrome can be induced by a small amount of platelets contaminating a red blood cell transfusion or, occasionally, following fresh frozen plasma transfusion. The thrombocytopenia responds to intravenous immunoglobulin (IVIG). Other platelet alloantigens are occasionally implicated in posttransfusion purpura.

Neonatal alloimmune thrombocytopenia

The prevalence of neonatal alloimmune thrombocytopenia is approximately 1 case in 200 term pregnancies; for clinically apparent disease, the prevalence is 1 case in 1500 term pregnancies. It is the most common cause of severe neonatal thrombocytopenia. Maternal antibodies against the fetal platelet antigens, inherited from the father but absent in the mother, cross the placenta and induce severe thrombocytopenia.

Typically, the diagnosis is considered when bleeding or severe thrombocytopenia occurs in a baby after an otherwise uncomplicated pregnancy. The affected infant may have intracranial hemorrhage, and the disorder is associated with a relatively high mortality rate. The platelet count should be checked immediately after delivery and 24 hours later as it continues to fall.

Drug-induced thrombocytopenia

Drugs can induce thrombocytopenia by a number of mechanisms. In addition to the cytotoxic drugs, thiazide diuretics, interferon, and alcohol can cause thrombocytopenia by inhibiting platelet production in the bone marrow. More commonly, drug-induced thrombocytopenia results from the immunological destruction of platelets. Drugs can induce antibodies to platelets, either acting as a hapten or as an innocent bystander. Also, drugs such as gold salts and interferon can induce an ITP-like disorder.

Common drugs associated with thrombocytopenia include quinidine, amiodarone, gold, captopril, sulfonamides, glibenclamide, carbamazepine, ibuprofen, cimetidine, tamoxifen, ranitidine, phenytoin, vancomycin, and piperacillin.

Thrombotic thrombocytopenic purpura

TTP is a rare but serious disorder that was initially described as a pentad of thrombocytopenia (with purpura), red blood cell fragmentation, renal failure, neurological dysfunction, and fever. Recent evidence indicates that this disorder results from the abnormal presence of unusually large multimers of von Willebrand protein. These ultra-large precursors, normally synthesized in the endothelial cells, are processed by a plasma enzyme to normal-sized multimers. This enzyme is now identified as ADAMTS13, a metalloproteinase synthesized in the liver.

Hemolytic uremic syndrome

Patients with hemolytic uremic syndrome (HUS) have vascular lesions indistinguishable from those observed in patients with TTP, but the renal vasculature endures the most lesions, with minimal neurological dysfunction. This is a catastrophic illness that predominantly affects children aged 4-12 months, sometimes affects older children, and rarely affects adults. It follows an upper respiratory tract infection. In the tropics, epidemics of HUS are frequent and resemble an infectious disease; however, no causative organism has been identified. In North America, Shigella-like toxins (secreted by Escherichia coli serotype 0157:H7 or Shigella dysenteriae serotype I) cause many cases of HUS. Diarrhea and abdominal cramps are very prominent symptoms.

Disorders of platelet function

Functional disorders of platelets are relatively rare, and most of these disorders are mild and may not be recognized early in life.

von Willebrand disease

von Willebrand disease is the most common inherited bleeding disorder. It is autosomal dominant, and its prevalence is estimated to be as high as 1 case per 1000 individuals.

The hallmark of von Willebrand disease is defective platelet adhesion to subendothelial components caused by a deficiency of the plasma protein vWf. This factor is a large, multimeric protein synthesized, processed, and stored in the Weibel-Palade bodies of the endothelial cells, and it is secreted constitutively following stimulation. vWf has a major role in primary hemostasis as mediator of the initial shear-stress–induced interaction of the platelet to the subendothelium via the glycoprotein Ib complex. In addition, von Willebrand protein acts as a carrier and stabilizer of coagulation factor VIII by forming a complex in the circulation. In the absence of vWf, the factor VIII level is low. In classic hemophilia A, the factor VIII level is low because of a deficiency of factor VIII itself, whereas in von Willebrand disease, the factor VIII level is low because of a deficiency in its carrier protein

Bleeding time is prolonged in persons with von Willebrand disease. Because the von Willebrand protein is phase-reactant (ie, increased synthesis in the presence of inflammation, infection, tissue injury, and pregnancy), a mild prolonged bleeding time may be normalized, resulting in difficulty in diagnosis.

In addition to the prolonged bleeding time, characteristic abnormalities in platelet aggregation tests occur. In patients with von Willebrand disease, platelets aggregate normally to all agonists except ristocetin. The antibiotic ristocetin induces binding of the von Willebrand protein to platelets, similar to what happens with platelets following vessel wall injury in vivo. Ristocetin-induced platelet aggregation correlates with the platelet-aggregating activity of the von Willebrand protein. Levels of coagulation factor VIII are also low, resulting from a decrease in vWf.

Platelet dysfunction in uremia

Abnormal bleeding is common in patients with uremia. The bleeding has the characteristics of a platelet disorder, and GI tract bleeding is the most frequent symptom.

Platelet Disorders

Bleeding time is generally very prolonged in patients with uremia, signifying a major defect in platelet function, which improves after dialysis. A number of dialyzable platelet-inhibitory factors have been shown to inhibit platelet function. Furthermore, uremic platelets synthesize less thromboxane A2, and the blood vessels taken from patients with uremia produce greater quantities of platelet-inhibitory prostaglandin. Nitric oxide produced by the endothelial cells inhibits platelet function. Because the prolonged bleeding time and the hemostatic abnormalities are partly corrected by red blood cell transfusion or erythropoietin therapy, the failure of hemoglobin to quench excess nitric oxide synthesis has been suggested as partly responsible for the platelet dysfunction.

Frequency:

Sex:

History:

Physical:

 

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Purpuric spots

Lab Studies:

 

 

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 Spurious thrombocytopenia. Peripheral smear of a patient reported to have platelet counts of 10,000-150,000/mL on various occasions. The smear shows clumping of the platelets and satellitism involving neutrophils and platelets

 

 

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Examination of the peripheral smears in immune thrombocytopenic purpura often shows giant platelets. These platelets reflect the increased megakaryocytic mass in the marrow.

 

 

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Peripheral smear of a patient with Bernard-Soulier syndrome showing giant platelets. These platelets are not counted as platelets in most particle counters.

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Examination of the peripheral smear shows red blood cell fragments, basophilic cells, in addition to thrombocytopenia in thrombotic thrombocytopenic purpura

Other Tests:

Bone marrow examination in patients with ITP shows megakaryocytic hyperplasia . Quantifying the megakaryocytes in the bone marrow is technically difficult. Usually, 2-3 megakaryocytes are present in each spicule in typical marrow. Clusters of immature megakaryocytes are often observed in patients with ITP.

 

 

 

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Bone marrow in immune thrombocytopenic purpura. Bone marrow examination reveals an increased number of megakaryocytes.

Medical Care:

 

 

 

Thrombocytopenic purpura (Werlhof's disease). Thrombocytopenic purpura is a haemorrhagic diathesis due to the deficit of blood platelets. The disease was first described by Paul Werlhof in 1735. Throm­bocytopenic purpura occurs mostly in young females.

The aetiology and pathogenesis of the disease are unknown. It has only been established that the immune-allergic mechanism is positively involved in about 50 per cent cases: anti-thrombocytic antibodies are produced and fixed on the surface of thrombocytes to damage them and to prevent their normal separation from megakaryocytes. The triggering factors (the im­petus to production of auto-antibodies) may be infection, toxicosis, individual hypersensitivity to certain foods and medicines. In some cases the disease is caused by hereditary insufficiency of certain enzyme thrombocyte systems which is probably activated by some additional factors.

Pathological anatomy. Multiple haemorrhages in the skin and the internal organs are characteristic. The spleen may be considerably enlarged. Separation of thrombocytes from megakaryocytes in the bone marrow is disordered (according to histological findings).

Clinical picture. The main symptom of the disease is the appearance on the skin and mucosa of multiple haemorrhages in the form of small dots (petechiae) or large spots (ecchymoses). Haemorrhage may be spontaneous and due to insignificant injuries, mild contusion, pressure on the skin, etc. Haemorrhagic lesions are first purple, then they darken to cherry-red and brown, and then lighten to yellow and disappear in several days. But new lesions develop to succeed the disappearing ones. Bleeding from the nose, gastro-intestinal tract, kidneys or uterus are not infrequent; haemorrhages into the internal organs (brain, fundus oculi, myocardium, etc.) are also possible. Grave and prolonged bleedings arise in extraction of teeth or in other minor operations. The tourniquet test (and especially the pinch test) are positive. The spleen and the lymph nodes are usually not enlarged; tapping on the bones is painless.

Thrombocyte counts are usually less than 50 x 109 per 1 1; in some cases only single blood platelets can be found in preparations. The degree  of bleeding can be assessed by the degree of thrombocytopenia. Hypochromic anaemia can develop after profuse bleeding. The clotting time is normal in most cases, but it can be slightly longer (due to the deficit of thromboplastic factor III of blood platelets). The bleeding time increases to 15-20 min and more; clot retraction is disordered. Throm-boelastography reveals greatly increased reaction and clotting time.

 

THROMBOCYTOPENIA

Thrombocytopenia is caused by one of three mechanisms-decreased bone marrow production, increased splenic sequestration, or accelerated destruction of platelets. In order to determine the etiology of thrombocytopenia, each patient should have a careful examination of the peripheral blood film, an assessment of marrow morphology by examination of an aspirate or biopsy, and an estimate of splenic size by bedside palpation supplemented, if necessary, by ultrasonography or computed tomographic (CT) scan. Occasional patients have "pseudothrombocytopenia," a benign condition in which platelets agglutinate or adhere to leukocytes when blood is collected with EDTA as anticoagulant. This is a laboratory artifact, and the actual platelet count in vivo is normal.

Impaired Production  Disorders that injure stem cells or prevent their proliferation frequently cause thrombocytopenia. They usually affect multiple hematopoietic cell lines so that thrombocytopenia is accompanied by varying degrees of anemia and leukopenia. Diagnosis of a platelet production defect is readily established by examination of a bone marrow aspirate or biopsy, which should show a reduced number of megakaryocytes. The most common causes of decreased platelet production are marrow aplasia, fibrosis, or infiltration with malignant cells, all of which produce highly characteristic marrow abnormalities. Occasionally, thrombocytopenia is the presenting laboratory abnormality in these disorders. Cytotoxic drugs impair megakaryocyte proliferation and maturation and frequently cause thrombocytopenia. Rare marrow disorders such as congenital amegakaryocytic hypoplasia and thrombocytopenia with absent radii (TAR syndrome), produce a selective decrease in megakaryocyte production.

Splenic Sequestration  Since one-third of the platelet mass is normally sequestered in the spleen, splenectomy will increase the platelet count by 30%. Postsplenectomy thrombocytosis is a benign self-limited condition that does not require specific therapy. In contrast, when the spleen enlarges, the fraction of sequestered platelets increases, lowering the platelet count. The most common causes of splenomegaly are portal hypertension secondary to liver disease and splenic infiltration with tumor cells in myeloproliferative or lymphoproliferative disorders. Isolated splenomegaly is rare, and in most patients it is accompanied by other clinical manifestations of an underlying disease. Many patients with leukemia, lymphoma, or a myeloproliferative syndrome have both marrow infiltration and splenomegaly and develop thrombocytopenia from a combination of impaired marrow production and splenic sequestration of platelets.

Accelerated Destruction  Abnormal vessels, fibrin thrombi, and intravascular prostheses can all shorten platelet survival and cause nonimmunologic thrombocytopenia. Thrombocytopenia is common in patients with vasculitis, the hemolytic uremic syndrome (HUS), thrombotic thrombocytopenic purpura (TTP), or as a manifestation of disseminated intravascular coagulation (DIC). In addition, platelets coated with antibody, immune complexes, or complement are rapidly cleared by mononuclear phagocytes in the spleen or other tissues, inducing immunologic thrombocytopenia. The most common causes of immunologic thrombocytopenia are viral or bacterial infections, drugs, and a chronic autoimmune disorder referred to as idiopathic thrombocytopenic purpura (ITP). Patients with immunologic thrombocytopenia do not usually have splenomegaly and have an increased number of bone marrow megakaryocytes.

 

DRUG-INDUCED THROMBOCYTOPENIA

Many common drugs can cause thrombocytopenia. Cancer chemotherapeutic agents may depress megakaryocyte production. Ingestion of large quantities of alcohol has a marrow-depressing effect leading to transient thrombocytopenia, particularly in binge drinkers. Thiazide diuretics, used to treat hypertension or congestive heart failure, impair megakaryocyte production and can produce mild thrombocytopenia (50,000 to 100,000/uL), which may persist for several months after the drug is discontinued.

Most drugs induce thrombocytopenia by eliciting an immune response in which the platelet is an innocent bystander. The platelet is damaged by complement activation following the formation of drug-antibody complexes. Current laboratory tests can identify the causative agent in 10% of patients with clinical evidence of drug-induced thrombocytopenia. The best proof of a drug-induced etiology is a prompt rise in the platelet count when the suspected drug is discontinued. Patients with drug-induced platelet destruction may also have a secondary increase in megakaryocyte number without other marrow abnormalitie.

Although most patients recover within 7 to 10 days and do not require therapy, occasional patients with platelet counts <10,000 to 20,000/uL have severe hemorrhage and may require temporary support with glucocorticoids, plasmapheresis, or platelet transfusions while waiting for the platelet count to rise. A patient who has recovered from drug-induced immunologic thrombocytopenia should be instructed to avoid the offending drug in the future, since only minute amounts of drug are needed to set up subsequent immune reactions. Certain drugs that are cleared from body storage depots quite slowly, such as phenytoin, may induce prolonged thrombocytopeni.

Heparin is a common cause of thrombocytopenia in hospitalized patients. Between 10 and 15% of patients receiving therapeutic doses of heparin develop thrombocytopenia and, occasionally, may have severe bleeding or intravascular platelet aggregation and paradoxical thrombosis. Heparin-induced thrombosis, sometimes called the "white clot syndrome," can be fatal unless recognized promptly. Most cases of heparin thrombocytopenia are due to drug-antibody binding to platelets; some are secondary to direct platelet agglutination by heparin. The offending antigen is a complex formed between heparin and the platelet-derived heparin neutralizing protein, platelet factor 4. Prompt cessation of heparin will reverse both thrombocytopenia and heparin-induced thrombosis. Low-molecular-weight heparin products have reduced the incidence of heparin-induced thrombocytopenia. They are effective antithrombotic agents and are less immunogenic. Unfortunately, 80 to 90% of the antibodies generated against conventional heparins cross-react with low-molecular-weight heparins, so only a minority of patients with preformed antibody can be treated with this product.

 

IDIOPATHIC THROMBOCYTOPENIC PURPURA

The immunologic thrombocytopenias can be classified on the basis of the pathologic mechanism, the inciting agent, or the duration of the illness. The explosive onset of severe thrombocytopenia following recovery from a viral exanthem or upper respiratory illness (acute ITP) is common in children and accounts for 90% of the pediatric cases of immunologic thrombocytopenia. Of these patients, 60% recover in 4 to 6 weeks and >90% recover within 3 to 6 months. Transient immunologic thrombocytopenia also complicates some cases of infectious mononucleosis, acute toxoplasmosis, or cytomegalovirus infection and can be part of the prodromal phase of viral hepatitis and initial infection with HIV. Acute ITP is rare in adults and accounts for <10% of postpubertal patients with immune thrombocytopenia. Acute ITP is caused by immune complexes containing viral antigens that bind to platelet Fc receptors or by antibodies produced against viral antigens that cross-react with the platelet. In addition to these viral disorders, the differential diagnosis includes atypical presentations of aplastic anemia, acute leukemias, or metastatic tumor. A bone marrow examination is essential to exclude these disorders, which can occasionally mimic acute ITP.

 

 

Hematomas

 

Course. Both acute and chronic recurrent forms of the disease are observed. The patient dies of profuse bleeding and haemorrhages into the vital organs.

Treatment. Removal of the spleen is indicated in grave ca^es: the number of thrombocytes increases in the blood of a patient and haemor­rhage stops in a few days following the operation. The effect of splenec­tomy is probably explained by decreased decomposition of blood platelets in the spleen and by the removal of the inhibiting effect that the spleen has on thrombocytopoiesis. Blood transfusion is useful for haemostasis and blood substitution. Repeated transfusion of thrombocytic mass gives positive haemostatic effect. Vitamin P, vitamin C, calcium chloride and vicasol are given to strengthen the vascular walls. Since the allergic factor is involved in the pathogenesis of the disease, corticosteroid hormones are quite effective in certain cases.

 

 

FACTOR VIII DEFICIENCY-HEMOPHILIA A

Pathogenesis and Clinical Manifestations.  The antihemophilic factor (AHF), or factor VIII coagulant protein, is a large (265-kDa), single-chain protein that regulates the activation of factor X by proteases generated in the intrinsic coagulation pathway. It is synthesized in liver and circulates complexed to the von Willebrand factor (vWF) protein. Factor VIII molecule is present in low concentration (10 ug/L) and is susceptible to proteolysis. The gene for factor VIII is on the X chromosome, and carrier detection and prenatal diagnosis are well established.

One in 10,000 males is born with deficiency or dysfunction of the factor VIII molecule. The resulting disorder, hemophilia A, is characterized by bleeding into soft tissues, muscles, and weight-bearing joints. Symptomatic patients usually have factor VIII levels <5%, with a close correlation between the clinical severity of hemophilia and plasma AHF level. Patients with <1% factor VIII activity have severe disease; they bleed frequently even without discernible trauma. Patients with levels of 1 to 5% have moderate disease with less frequent bleeding episodes. Those with levels >5% have mild disease with infrequent bleeding that is usually secondary to trauma. Occasional patients with factor VIII levels as high as 25% are discovered when they bleed after major trauma or surgery. The majority of patients with hemophilia A have factor VIII levels below <5%.

Hemophilic bleeding occurs hours or days after injury, can involve any organ, and, if untreated, may continue for days or weeks. This can result in large collections of partially clotted blood putting pressure on adjacent normal tissues and can cause necrosis of muscle (compartment syndromes), venous congestion (pseudophlebitis), or ischemic damage to nerves. Patients with hemophilia often develop femoral neuropathy due to pressure from an unsuspected retroperitoneal hematoma. They can also develop large calcified masses of blood and inflammatory tissue that are mistaken for cancers (pseudotumor syndrome).

Patients with severe hemophilia are usually diagnosed shortly after birth because of an extensive cephalhematoma or profuse bleeding at circumcision. However, young children with moderate disease may not bleed until they begin to walk or crawl, and individuals with mild hemophilia may not be diagnosed until they are adolescents or young adults. Typically, a hemophilia patient presents with pain followed by swelling in a weight-bearing joint, such as the hip, knee, or ankle. The presence of blood in the joint (hemarthrosis) causes synovial inflammation, and repetitive bleeding erodes articular cartilage and causes osteoarthritis, articular fibrosis, joint ankylosis, and eventually muscle atrophy. Bleeding may occur into any joint, but after a joint has been damaged, it may become a site for subsequent bleeding episodes.

Hematuria, without any genitourinary pathology, is also common. It is usually self-limited and may not require specific therapy. The most feared complications of hemophilia are oropharyngeal and central nervous system bleeding. Patients with oropharyngeal bleeding may require emergency intubation to maintain an adequate airway. Central nervous system bleeding can occur without antecedent trauma or without evidence of a specific lesion.

Patients suspected of having hemophilia should have a platelet count, bleeding time, PT, and PTT. Typically, the patient will have a prolonged PTT with all other tests normal. Because of the clinical similarity of factor VIII deficiency and factor IX deficiency, any male with an appropriate bleeding history and a prolonged PTT should have specific assays for factor VIII and factor IX.

 

FACTOR IX DEFICIENCY-HEMOPHILIA B

Factor IX is a single-chain, 55-kDa proenzyme that is converted to an active protease (IXa) by factor XIa or by the tissue factor-VIIa complex. Factor IXa then activates factor X in conjunction with activated factor VIII. Factor IX is one of six proteins synthesized in the liver that require vitamin K for biologic activity. Vitamin K is a cofactor for a unique posttranslational modification that inserts a second carboxyl group onto certain glutamic acid residues on factor IX. This modification permits calcium binding and adsorption onto phospholipid surfaces. Factor IX gene is on the X chromosome.

Factor IX deficiency or dysfunction (hemophilia B, Christmas disease) occurs in 1 in 100,000 male births. Accurate laboratory diagnosis is critical, since it is indistinguishable clinically from factor VIII deficiency (hemophilia A) but requires different treatment. Either fresh-frozen plasma or a plasma fraction enriched in the prothrombin complex proteins is used. Monoclonally purified or recombinant factor IX preparations are now available. In addition to the expected complications of hepatitis, chronic liver disease, and AIDS, the therapy of factor IX deficiency has a special hazard. Trace quantities of activated coagulation factors in prothrombin complex concentrates may activate the coagulation system and cause thrombosis and embolism. This is particularly common in immobilized surgical patients and patients with liver disease. As a result, some centers have returned to fresh-frozen plasma for factor IX-deficient surgical patients, while others have recommended the addition of small doses of heparin to the concentrate to activate antithrombin III during the infusion and reduce hypercoagulability. The recombinant or monoclonally purified products are less likely to be thrombogenic.

 

FACTOR XI DEFICIENCY

Factor XI is a 160-kDa dimeric protein activated to an active protease (XIa) by factor XIIa, in conjunction with high-molecular-weight kininogen and kallikrein. Factor XI deficiency is inherited as an autosomal recessive trait and is especially common in Ashkenazi Jews. In contrast to deficiency in factors VIII and IX, the correlation between factor level and propensity to bleed is not as precise, spontaneous bleeding is less, and hemarthroses are rare. Many patients with factor XI deficiency present with posttraumatic bleeding or with bleeding in the perioperative period, and occasional factor XI-deficient women have menorrhagia. Daily infusions of fresh-frozen plasma are sufficient, since the half-life of factor XI is approximately 24 h. The majority of defective factor XI alleles were accounted for by a limited number of mutations.

 

OTHER FACTOR DEFICIENCIES

Deficiencies in factors V, VII, X, and prothrombin (factor II) are exceedingly rare autosomal recessive disorders. Spontaneous or posttraumatic musculoskeletal bleeding or menorrhagia can occur with these deficiencies, but hemarthroses are uncommon. Fresh-frozen plasma is the appropriate therapy, although prothrombin concentrates may be employed for patients with severe prothrombin deficiency or decreases in factors VII and X as long as the risks of hepatitis and thrombosis are recognized.

Defects in the contact activation pathway involving Hageman factor (factor XII), high-molecular-weight kininogen, and prekallikrein cause laboratory abnormalities but no clinical bleeding. Despite dramatic prolongation of the PTT, often to greater than 100 s, deficient individuals have normal hemostasis and can undergo major surgery without plasma replacement therapy. Direct activation of factor IX by the tissue factor-VIIa complex may bypass this defective step in coagulation. Recognition of these disorders is important because such patients should neither be treated inappropriately with plasma nor denied indicated surgery on the basis of these laboratory abnormalities.

Hemophilia

Hemophilia A (HA) is considered the classic form of hemophilia, and hemophilia B (HB) is termed Christmas disease. HA is a consequence of a congenital deficiency of factor VIII (FVIII), and HB is a consequence of a congenital deficiency of factor IX (FIX). This deficiency results in insufficient generation of thrombin by FIXa and FVIIIa complex through the intrinsic pathway of the coagulation cascade. For more information on factor deficiencies, see Factor XIII and Factor IX.

The classification of the severity of hemophilia has been based on either clinical bleeding symptoms or on plasma procoagulant levels, which are the most widely used criteria. Persons with less than 1% normal factor (<0.01 IU/mL) are considered to have severe hemophilia. Persons with 1-5% normal factor (0.01-0.05 IU/mL) are considered to have moderately severe hemophilia. Persons with more than 5% but less than 40% normal factor (>0.05 to <0.40 IU/mL) are considered to have mild hemophilia. Clinical bleeding symptom criteria have been used because patients with FVIII or FIX levels less than 1% occasionally have little or no spontaneous bleeding and appear to have clinically moderate or mild hemophilia. Furthermore, the reverse is true for patients with procoagulant activities of 1-5%, who may present with symptoms of clinically severe disease.

History:

Physical:

Causes:

Lab Studies:

Procedures:

Histologic Findings: Recurrent joint bleeds result in synovial hypertrophy, hemosiderin deposition, fibrosis, and damage to cartilage.

Staging: Hemophilic arthropathy evolves through 5 stages, starting as an intra-articular and periarticular edema due to acute hemorrhage and progressing to stage 5, which consists of advanced erosion of the cartilage with loss of the joint space, joint fusion, and fibrosis of the joint capsules.

Medical Care: Before a patient with hemophilia is treated, the following information should be obtained: (1) the type and severity of factor deficiency, (2) the nature of the hemorrhage or the planned procedure, (3) the patient's previous treatments with blood products, (4) the presence and possible titers of inhibitors, and (5) the patient's previous history of desmopressin acetate (DDAVP) use (eg, in mild HA only) with the degree of response and clinical outcome.

Various FVIII and FIX concentrates are now available to treat HA and HB. Reductions in infectious complications and improved purity are the main advantages of these concentrates. During production, a specific viral-inactivation stage, either solvent-detergent treatment or liquid-phase heat treatment, is implemented to inactivate viruses, such as hepatitis B virus, hepatitis C virus, and HIV. However, the transmission of nonenveloped viruses (eg, parvovirus and hepatitis A virus) and poorly characterized agents (eg, prions) is still a problem.

Recombinant FVIII and FIX are now commercially available. They have lowered the risk of viral contamination.

Consultations:

Activity:

 

Haemophilic arthropathy of knee joint

(²²²-²Ó stage)

 


Ankilosis of knee joint in haemophylia

 

 

 

 

Femoral joints arthropathy in hemophilia

Treatment

Medical Care: FVIII replacement is used for acute bleeding, perioperatively for prevention of bleeding during planned surgical procedures, for prophylaxis to prevent recurrent bleeding of target joints, in early institution of childhood prophylactic therapy to preserve long-term joint function, or for immune tolerance induction (ITI) regimens. Prompt and adequate therapy for bleeding is essential to avoid the long-term destructive consequences of joint bleeding.

Home-care programs have made patients self-sufficient in infusing product, with guidance and supervision from personnel at a hemophilia center or a knowledgeable physician in the local community. This has also improved quality of life by minimizing the time spent in hospital emergency departments, providing rapid and early therapy for acute bleeding, achieving a prompt reduction in pain due to early specific correction of the factor deficiency and joint immobilization, and allowing concomitant provision of appropriate narcotic and nonnarcotic analgesics. Joint integrity can be preserved with the start of early prophylactic home-care programs in childhood (maintain a minimum of 1-2% FVIII-C at all times by infusing replacement product at home 3 times/wk).

All of these allow a patient to participate in more of life's activities. The specific dose and duration of factor replacement therapy is determined by the location of the bleeding, severity of the bleeding, and known actual response to prior therapy.

Intermediate- or high-purity plasma-derived products are still available for use in patients who have previously used such products. Monoclonal antibody purified plasma–derived products are usually free of some viral contaminants. In children who are starting therapy for the first time or in persons with hemophilia who are negative for HIV, recombinant products are used whenever possible because of their presumed higher viral safety. Importantly, be aware that approximately 25% of the lots of human albumin containing first-generation recombinant FVIII concentrates have been found to be positive for transfusion-transmitted (TT) virus from contaminated human serum albumin. All second-generation recombinant FVIII preparations (free from human albumin) have been negative for the virus (Azzi, 2001).

See the Table and related material for a general dosing guide for replacement therapy and for target FVIII levels for acute bleeding. The duration of therapy depends on the site and cause of bleeding and response to therapy. Bolus dosing is still the most often used method of replacement, but a continuous infusion regimen generally reduces total administered doses by approximately 30%. Data on the lowest necessary dose for adequate therapy, a consideration because of the enormous cost of products, are being obtained (Srivastava, 1998).

Monitoring actual levels of FVIII-C is necessary to confirm the presence of adequate amounts of FVIII in vivo to correct hemostasis when (1) a patient is first treated, (2) a new product is being used, (2) the onset of an inhibitor is suggested, (4) active ongoing bleeding is present, or (5) persistence or inadequate correction of bleeding has been encountered with previously adequate doses.

Minor bleeding, as from cuts and abrasions, may respond to conservative measures, such as pressure and ice. Mild hematuria may subside spontaneously. Do not aspirate hematomas or joints or cauterize bleeding sites unless specifically indicated because these may aggravate the bleeding.

Epistaxis and moderately severe hematuria may be adequately treated by achieving and maintaining FVIII levels in the range of 30-50%. Use higher dosing initially, followed by a gradual lowering of the dose after bleeding is under control, and then continue FVIII replacement until clinical and objective evidence indicates resolution of the bleeding. Acute joint bleeding and expanding, large hematomas require adequate replacement for a prolonged period until the bleed begins to resolve, as evidenced by clinical and/or objective methods. Relief of the intense pain with joint bleeding frequently requires the use of narcotic analgesics; relief of pain also accompanies cessation of bleeding after adequate factor replacement.

Life-threatening bleeding episodes are generally initially treated with FVIII levels of approximately 100%, until the clinical situation warrants a gradual reduction in dosage. Continuous intravenous infusions avoid the low troughs and excesses of intermittent bolus dosing, maintain adequate levels at all times, and save approximately 30% of expensive product usage (Hathaway, 1984; Batorova, 2000).

For serious bleeding events, continue replacement for at least 7-10 days because of the potential risk of recurrent bleeding. A multiple-bolus drug dosing regimen model has been developed to better estimate loading and maintenance dose requirements to allow maintenance of a minimum trough level of FVIII at all times (Dedik, 2000). In patients who may have an intracranial hemorrhage, administer a full dose of factor concentrate before the patient is sent for any diagnostic radiologic procedures in order to avoid delays in bleeding control. Surgically drain intracranial bleeding promptly, as clinically dictated, following replacement therapy.

Patients with combined FV and FVIII deficiency require combined replacement with FVIII concentrates and FFP for FV, which also supplies a small amount of FVIII. Deamino-8-D-arginine vasopressin (DDAVP) to raise FVIII (without concomitant FVIII concentrate) in combination with FFP as a source of FV has been used successfully in the perioperative management of an older Italian man who was undergoing surgical repair of massive bilateral inguinal hernias (McKenna, 1987). In current practice, pooled solvent-detergent–treated plasma (PLAS+ SD) is safer than standard FFP because the lipid enveloped viruses are removed.

Collaboration with an infectious disease consultant is a major need in caring for patients with HIV/AIDS or hepatitis. The serious psychiatric issues present in the management of patients infected with HIV may require the assistance of a psychiatrist (Treisman, 2001).

Simple immediate ancillary measures of ice, pressure, elastic bandage (ACE) wrap, immobilization of the affected joint, and avoidance of NSAIDs must not be forgotten.

The benefits of prophylaxis in the management of hemophilia A should be emphasized (Hoots and Nugent, 2006). There are clear advantages of prophylaxis for patients with hemophilia A compared to on-demand treatment, including a reduction in the number of bleeding episodes, improved joint function, and greater patient well-being. Sadly, there is a heavier economic burden with increased factor use.

 

 

Click to see larger picture

Quality of life! Child with hemophilia at summer camp

 

The scheme of a Case History.

The technique of inquiry of a patient

General inspection of a petient. Diagnostic meaning of symptoms obtained by inspection of a patient

Inspection of separate parts of patient’s body: head, neck, trunk, limbs

 

 

Sequence of interviewing.

The Case History consist of such components as: the identifying data, the main complaints, the history of present illness, the past medical history, the review of systems. The outlined compounds of a case history, being used in the correct order, help to obtain the organized set of data about patient’s condition and disease.

 

Identifying Data and their diagnostic value

Identifying Data include at least age, sex, race, place of birth, present address, marital status, occupation (profession).

 

Patient¢s complaints and their detalization

You should collect main patient’s complaints, when possible, in patient’s own words, and then describe their characteristics. The principal symptoms should be described in terms of their location, quality, quantity or severity, timing (i.e., onset, duration, and frequency), setting, factors that have aggravated or relived these symptoms, and associated manifestations. Then find out and analyze the general complaints. For example, weakness, high body temperature, etc. 

The chief complaint represents the specific reason for the patient’s visit to the clinic, office, or hospital. The chief complaint may be viewed as the theme, with the present illness as the setting of this problem. Six guidelines determine appropriate recording of the chief complaint: (1) it consists of a brief statement, (2) it is restricted to one or two symptoms, (3) it refers to a concrete complaint, (4) it is recorded in the patient’s or parent’s own words, (5) it avoids the use of diagnostic terms or translations, and (6) it states the duration of the symptoms.

The doctor elicits the chief complaint by asking open-ended neutral questions such as, “Tell me what seems to be the matter?”, “How may I help you?” or “What brings you here?”  Labeling-type questions such as, “How are you sick?” should be avoided, since it is possible that the reason for the visit is not because of illness. For example, the visit may be for a routine health assessment, or the chief complaint may be of a nonphysical nature.

Examples of properly recorded chief complaints for a variety of situations may be: (1) ambulatory clinic – “My patient has had a runny nose and sore throat for 4 days, but today it is worse”, (2) hospital admission – “I need to have my tonsils fixed”, sore throat and repeated earaches for 5 years, and (3) health center – “We are here for a routine checkup”, last visit 1 year ago.

If the visit is for  examination, one can ask, “Before we begin, is there anything of particular concern that you would like to discuss?”. This type of statement encourages the parent (or patient) to bring up an issue that may not surface during routine interviewing.

Occasionally it is difficult to isolate one symptom or problem as the chief complaint because the parent may identify many. In this situation it is important to be as specific as possible when asking questions. For example, asking informants to state which one problem or symptom caused them to seek help now may help them to focus on the most immediate concern.

Example of patients complaints description:

In case, if you have been visited by a patient with chronic pyelonephritis, its possible, that the result of the examination would be the following:

The patient R. complains of a constant dull pain in the lumbar region (noniradiating); it remits after taking Baralginum, No-spa and it increases after taking spicy or salty food; constant rise of body temperature up to 37,80C, chill, frequent urination (up to 10 times a day). Besides, the patient complains of general weakness, insomnia, depression of working ability.

 

 

 

Patient’s present illness history

  The history of present illness is a clear,  chronological narrative  account  of the problems which the patient is seeking care for. It should include the onset of the problem, the setting in which they was developed, their manifestations,  treatment, their impact upon the patient’s life, and meaning to the patient. Relevant data from the patient’s chart, such as laboratory reports, also belong in the present illness.

The history of the present illness is a narrative of the chief complaint from its earliest onset through its progression to the present. Its four major components are (1) details of onset, (2) complete interval history, (3) present status, and (4) reason for seeking help now. The focus of the present illness is on all those factors that are relevant to the main problem, even if they have disappeared or changed during the onset, interval, and present.

Analyzing a symptom. Since pain is often the most characteristic symptom denoting onset of a physical problem, it is used as a prototype for analysis of a symptom. The doctor should assess pain for (1) type, (2) location, (3) severity, (4) duration, and (5) influencing factors. The type or character of pain should be as specific as possible.

By type  pain may be sharp, throbbing, dull, aching, stabbing, and so on. Whatever words they use should be recorded in quotes.

The location of the pain also must be specific. “Stomach pains” is too general description. Sometimes it is necessary to ask to “point with one finger to where it hurts”. The doctor can also determine if the pain radiates by asking, “Does the pain stay there or move? Show me where it goes with your finger“.

The severity of pain is best determined by finding out how it affects the patient’s usual behavior. It is preferable to record pain in terms of interference with activity.

Duration of pain should include the duration, onset, and frequency of attacks. Influencing factors are anything that causes a change in the type, location, severity, or duration of the pain. These include (1) precipitating factors (those that cause or increase the pain), (2) relieving factors (those that lessen the pain, such as medications), (3) temporal events (times when the pain is relieved or increased), (4) positional events (standing, sitting, lying down, and so on), and (5) associated events (meals, stress, coughing, and so on).

A standard method of analyzing a symptom is listed in the following outline. These three categories - onset, characteristics, and course since onset - comprise the essential data for the present illness. Although the analysis of a symptom has concentrated on discussion of physical complaints, the same process of description and investigation can be used for emotional or psychosocial problems.

 

Analysis of a symptom

                   I.      Onset

a)          Date of onset,

b)         Manner of onset (gradual or sudden),

c)          Precipitating and predisposing factors related to onset (emotional disturbance, physical exertion, fatigue, bodily function, pregnancy, environment, injury, infection, toxins and allergens, therapeutic agents, and so on).

               II.       Characteristics

a)            Character (quality, quantity, consistency, or others),

b)           Location and radiation (of pain),

c)            Intensity or severity,

d)           Timing (continuous or intermittent, duration of each, temporal relationship to other events),

e)            Aggravating and relieving factors,

f)             Associated symptoms.

III. Course since onset

a)           Incidence

·          Single acute attack.

·          Recurrent acute attacks.

·          Daily occurrences.

·          Periodic occurrences.

·          Continuous chronic episode.

b)           Progress (better, worse, unchanged),

c)           Effect of therapy.

 

Past history:

The general state of health:

Previous diseases including viral hepatitis, sexual-transmitted diseases, infectious diseases within the last month, AIDS-risk factors

2. Immunizations: tetanus, diphtheria, polio etc.

3. Adult illness, operations, injuries, allergies.

4. Current medications, including home remedies, nonprescription drugs, and medicines borrowed from family or friends. When patient seems likely to be taking one or more medications, survey one 24-hour period in detail.

5. Diet.

6. Sleep Patterns. Including times that the person goes to bed and awakens, difficulties in failing asleep or staying asleep, and daytime naps.

7. Habits, including exercise and the usage of coffee, alcohol, other drugs, and tobacco.

8. The Family History:

The age and health, or age and cause  of death of each immediate family member (i.e., parents, siblings, and patients). Data on grandparents or grandchildren may also be useful.

The occurrence in the family of any of the following conditions: diabetes, tuberculosis, heart disease,  high blood pressure, kidney disease, cancer, arthitis, anemia, headaches, mental illness, or symptoms like those of the patient.

Social History: assessment of the home and job environment, professional hazards.

  Review of Systems: the relevant items are limited, but expand as the patient’s age increases.

 Systems ‘reviewing:

Carrying out the reviewing of systems you should pay attention to the following:

  1. General state of health: weight, recent weight change, weakness, fatigue, fever.

2. Skin: Rashes, lumps, itching, dryness, color changes, changes in hair or nails.

3. Head: Headache, head injury.

4. Eyes: Vision, glasses or contact lenses, last eye examination, pain, redness, excessive tearing, double vision, glaucoma, cataracts.

5. Ears: Hearing, tinnitus, vertigo, earaches, infection, discharge.

6. Nose and sinuses. Frequent colds, nasal stuffiness,   hay  fever, noseblends, sinus trouble.

7.  Mouth and throat. Condition of teeth,  last  dental  examination, sore tongue, frequent sore throats.

8. Neck: Lumps in neck swollen glands, pain in the neck.

9. Breasts: Lumps, pain, nipple discharge, self-examination

10. Respiratory system: Cough, sputum (color, quantity), hemoptysis, wheezing, asthma, bronchitis, emphysema, pneumonia, tuberculosis, pleurisy, tuberculin test; last chest x-ray film.

11. Cardiovascular system: high blood pressure, rheumatic fever, heart murmurs; dyspnea, orthopnea, paroxysmal nocturnal dyspnea, edema; chest pain, palpitations; past electrocardiogram or other heart tests

         12. Gastrointestinal system: Appetite, nausea, vomiting, vomiting of blood, indigestion, frequency of bowel movements, change in bowel habits, rectal bleeding or black tarry stools, constipation, diarrhea; abdominal pain, food intolerance, meteorism, hemorrhoids; jaundice, liver or gallbladder trouble, hepatitis.

13. Urinary: Frequency of urination, polyuria, nocturia, dysuria, hematuria, urgency, hesitancy, incontinence; urinary infections, stones.

14. Genito-reproductive:

Male: Discharges, history of venereal disease and its treatment, hernias, testicular pain; sexual difficulties.

Female: Age at menarche; regularity, frequency, and duration of periods; amount of bleeding, bleeding between periods or after intercourse, last menstrual period; dysmenorrhea; age of menopause, menopausal symptoms, post-menopausal bleeding. Discharge, venereal disease and its treatment; Number of pregnancies, number of abortions (spontaneous and induced);complications of pregnancy; sexual difficulties.

15. Musculoskeletal system: Joint pains or stiffness, arthritis, backache..Muscle pain.

16. Periferal vessels: Intermittent claudication, cramps, varicose veins, thrombophlebitis.

17. Nervous system: Fainting, blackouts, paralysis, local weakness, tremors, memory.

18. Endocrine system: Thyroid trouble, heat or cold intolerance, excessive sweating, diabetes, excessive thirst, hunger, urination.

19. Hematologic: Anemia, easy bruising or bleeding, past transfusions and possible reactions and antibiotics.

 

A Scheme of Inquiry

Questioning a patient (Interrogatio)

 General information about a patient (Praefatio)

Name, surname

Sex

Age

Permanent address

Occupation

Place of employment

The name of referral institution

Date of admission to the hospital

Date of discharge from  the hospital

Patient’s complaints (Molestia aeqroti, Querellae aeqroti)

The main complaints are the main patient’s problems which he is suffered for. Every complaint should be defined with determination of its location, quality, quantity, severity, timing (onset, duration, frequency), the setting in which they occur, factors that have aggravated or relieved them, associated manifestations, any changes of these characteristics in dynamics, appearance of new symptoms.

Full description of complaints should be noted once for do not appaering need of searching different detalis in other parts of the Case History. A curator describes complaints of every system and details them concerning  main suffering system(s).

Then a curator describes in detalis the secondary complaints. To define them is possible only when a doctor asks patients additional questions because these complaints are not so severe.

Review of systems (Status praesens subjectivus)

Cardio-vascular system

Does the patient feel pain  in the heart region? If yes, you should define the following characteristics:

           -location (behind the sternum, above the apex, over the whole heart area);

           -when does it develop (on physical exertion, emotional overstrain, at rest);

                   -its irradiation (to the left arm, neck, left part of the neck, low jaw, intercapular space, left shoulder-blade);

           -characteristics of pain (acute, dull, constricting, stabbing, burning, pressing, boring, arching, or  a sense of heaviness);

-intensity (slight, of moderate intensity, strong, severe);

           -timing (persistent, periodical), if periodical - the frequency of its appearance  a day;

           -duration (during some minutes, hours, days);  

           -associated manifestations ;

           -provoking factors (physical or emotional overstrain);

           -factors that relieve or remove  pain;

-patient’s behavior during pain attack,body position that relieves pain.

Palpitation. If yes, what are its:

           -frequency (constant, paroxismal);

           -if periodical – duration of an attack, in what time and under what conditions does the attack develop: at physical overload, emotional overstrain, at rest, due to change in posture, without any  reason;

-when does it disappear?

           Is it followed by heart intermissions (a sense of  heart arrest,  heart disposition)? If yes-      what is the reason of these unpleasant feelings on the patient’s own opinion?

     Frequency of attacks a day, their duration, factors that relieve or remove the symptom.

 

Feeling of pulsations in different parts of patient’s body: its

-location, frequency, duration;

-relation to palpitation, heart intermissions, pain;

-provoking factors;

-factors that relieve or remove  symptom.

 

Does the patient complain of dyspnea? If yes, what is

           -the setting of its development (on exertion, during conversation, emotional overstrain, at rest)?

           -Its type (expiratory,  inspiratory or mixed);

           -is it attack-like or constant?

           -Is it more intensive in recumbent or upright position of the patient?

-Relation of dyspnea to body position (upright, recumbent), physical loading.

   

Suffocation: if present, define its

           -time of appearance (in day-time, at night);

           -frequency of attacks;

           -duration;

           -factors, that relieve the symptom;

           -what time and under what conditions does it develop (on exertion, emotional exertion, at night)?

 

Cough: time and condition of its appearance (in the morning, in the evening, at night);

           -timing (is it permanent or periodical), in the last case - duration and frequency of attacks;

           -loudness and intensity of cough (inssiculation, slight, of moderate intensity, loud);

           -character of cough (dry or with expectoration of sputum (moist);

           -under the what conditions does cough develop or become more severe, its relations to respiration, physical loading, singing, conversation etc.);

-factors that relieve or remove cough.

 

If cough is moist, define amount of sputum discharged per day and in one split;

           -peculiarities of discharging (is it heavy or easy, at what day time and in what body position sputum may be best discharged);

           -colour of sputum (greish, reddish);

           -smell of sputum;

           -are there any admixtures of blood in sputum, if yes, what is the degree of bleeding (blood streaks in sputum, sputum mixed with blood, pure blood in several splits, pronounced bleeding). Colour of  sputum should be clarified (light-red, dark), frequency of bleedings, duration, provoking factors, under the what conditions does bleeding become less intense  or disappear.

 

Edema: if present, what is its location?

           -time of appearance (in the morning, in the evening, all time);

           -under the what conditiond does in develip or become more pronounced (physical loading etc.)?

           -Factors, that relieve the symptom (due to usage of diuretics or on its own).

           -Relation of edema to water and salt intake.

Claudicatio intermittens: the time of appearance, relieving factors.

The signs of spasm of perypheral arteries: pain in the limbs, feeling of “freezing”, “numbness” of fingers, feeling of “dead” finger, headache, flickering before eyes.

 

Respiratory system

Does the patient breathe through the nostrils freely  or have any  difficulty in breathing ?

Dryness in the throat or behind the sternum (indicate, if present).

Does he (she) feel pain  in the chest, if yes, desribe, please, its location (with indication of topographic zones and lines);

-irradiation (toward which zone);

           -characteristic (acute, dull, stabbing, arching, pressing, boring, stretching, gnawing);

           -intensity (slight, of moderate intensity, strong, severe);

           -timing (constant, paroxismal)? In the last case – time of appearance;

           -provoking factors, especially the relation of pain to breathing movements, coughing, changes of body position;

           -factors that relieve or remove pain.

 

If patient complains of cough, you should determine its

           -time and condition of appearance (in the morning, in the evening, at night);

           -timing (is it persistent or fitlike), in the last case - duration and frequency of attacks;

           -loudness and tembre of cough (weak, of moderate loudness, loud, barking, loudless);

           -hacking cough (inssiculation);

           -character of cough (dry or with expectoration of sputum (moist).

 

If cough is moist, define: volume of sputum discharged per day and in one split;

           -peculiarities of discharging (is it heavy or easy, at what day time and in what body position is sputum discharged);

           -colour of sputum (greyish, yellowish, greenish, reddish);

           -does it smell of putridity?

           -Are there any admixtures of blood in sputum, if yes, what is the degree of bleeding (blood streaks in sputum, sputum mixed with blood, pure blood in several splits, pronounced bleeding);

           -colour of blood in sputum (light-red, dark, with raspberry hue, rusty).

 

Dyspnea: if present, define  following:

           -setting of its appearance (at rest or on exertion, degree of loading which conducts dyspnea);

           -is it permanent or periodical, in the last case – duration of attacks;

           -type of dyspnea (expiratory,  inspiratory or mixed);

           -provoking factors (smells, emotional strain, overcooling, physical exertion).

 

Suffocation; if present, define the following points:

           -aura: have been the patient ever noticed any previous symptomes like itching, dyspnea, nasal catarrh, sneezing or other before the attack?

           -When does the attack  occur?

           -Patient’s behavior and posture during the attack?

           -Duration, frequency, intensity  of attacks;

           -relieving factors (if the patient feels better after usage of medicines -  define the form of  usage: inhalations or injections).

 

Digestive system

What is patient’s appetite (good, moderate, increased, lack of appetite,  supressed, deranged, distaste for some kind of food (indicate it), fear of food intake).

Saturation: moderate, quick, permanent, constant feeling of hunger.

Mastication: deranged or preserved, pain at mastication (yes, no).

Does the patient complain of thirst? If yes, indicate its timing (constant or intermittent), when does it occure, relieving factors. The volume of water drunk per day.

 Salivation: its periodicity (permament or periodical), duration, when does it occure, relation to food intake, relieving factors.

Dryness in the mouth, pain and burning sensation in the tongue (yes, no).

Taste in the mouth:   normal, sour, bitter, metallic, sweet, deranged, perverted.

Swallowing and passage of food portion through the esophagus (painful, impossible or  difficult (does the difficulty depend on the sort of food – solid, liquid)?

 

Does the patient complain of pain in abdominal region? If yes, define its

           -location;

           -under which conditions does it appear?

           -Relation to the time of food intake (immediatelly after eating, in some minutes, 20-30 min, 40-50 min, in some hours,  “fasting” and “night” pain);

           -to the sort of food (fat, fried, spicy, milk, coarse, sweet) and its amount;

-characteristics of pain: acute, knife-like, dull, burning, boring, girdle, feeling of heaviness in the certain abdominal zone);

           -its intensity (slight, of moderate intensity, strong, severe);

           -irradiation;

           -time relationship (permament, periodical, undulate, seasonal);

           -duration of attacks (during some minutes, hours, days);

           -under what conditions does pain develop or become more intensive?

           -Relieving factors (vomiting, food intake, medications, intake of soda, applying of heat or  cold). In which body position does pain decrease?

           -Associated manifestations (changes of skin colour, urine, feces etc.).

 

Nausea: if present, detail the following:

           -does it preceed vomiting or not?

           -Is there any relation of nausea occurence to food intake (yes, no) and the sort of food (if yes, indicate the sort of food)?

 

If the patient complains of vomiting it is necessary to define the following:

           -time of its appearance (on the empty stomach, relation to  food intake: immediately after or late). Frequency of occurence, relation to pain;

           -provoking factors; relation to food intake, to the sort of food, relieving factors, does vomiting relieve patient’s condition?

           -Volume and character of emesis (with digested or indigested food, as a coffee ground, with admixtures of fresh blood, bile, mucus, foamy);

           -smell of the vomit if any (ammonia, bitter oil, acid, putrid, fecal, without any smell);

           -does vomiting relieve patient’s condition?

 

Regurgitation: if the patient suffers for, define the following:

           -time of its appearance (immediately after meals, some time after meals, after change of body position, on straining effort etc.);

           -character of regurgitation (gaseous, food, bitter or acid belching, musty smelling);

           -its duration, intensity, relieving factors.

 

In the case of heartburn define the frequency of its attacks,  

           -relation to food intake and the sort of food (immediately afer meals, after change of a position of the body);

           -relieving factors (taking baking soda, water, any drugs etc.).

 

Meteorisms: (present or absent);

           -does the patient feel abdominal murmur, fluctuation? If yes,  indicate  their location, under what conditions they develop or become more intensive, relation to food intake (indicate the sort of food) and to pain. Relieving factors;

           -passage of gasses through the intestine: free, difficult or impossible. Their smell (sharp, putrefied, acid). Relation to food intake, the kind of food and defecation.

 

Stool: define the following:

           -frequency of  defecation (frequent, regular, irregular, constipation, after enema);

           -a feeling of incomplete emptying of the bowels after defecation;

           -volume and consistence of stool (formed, fragmentation, semiliquid, ribbon shaped, watery, rie-water);

           -ñolour (brown, light, tarry)  and smell of feces;

           -admixtures if any (mucus, blood, pus, helminths, indigested food, foreign bodies);

           -in the case of blood discharging –does it occur during or after defecation; are feces mixed with blood or blood is present on the surface of feces;

           -tenesmus if any.

 

  Itching, anal pains if any: timing, duration, intensity, relation to defecation.

 

Urinary system

Pain in the lumbar region: its  character (dull, aching, acute, colicky);

           -is it permanent or attack-like?

           -Its irradiation, duration;

           -provoking and relieving factors.

 

Urination: define the following:

           -is urination normal or painful?

           -Frequency of urinations per day (general and separately during day- and  night-time);

           -the volume of water taken per day and discharged urina per day; correlation between daily and night diureses;

           -colour of urine (straw-yellow, “meat wastes”, “beer”);

           -smell  of urine;

           -urine sediment (present or absent, colour of sediments).

           Urinary incontinence if any: is it permanent or periodical, in the last case- its provoking factors (laughing,  coughing, drinking water etc.).

 

Endocrine system

Ask patient about the following:

Impairment from normal body growth and (or) fortmation of body build.

Any changes of body weight during last years, months (obesity, weight gain or loss, cachexia).

Ask about presence of the following signs: permanent thirst, hunger, dryness in the mouth, frequent urination, profuse urination, skin itching, white discharge, irritability, teafulness, palpitation, tremor of hands, inhibition.

Impairment of initial and secondary sexual signs.

Has the  patient ever noticed any changes of skin (profuse swetting or dryness, red skars, purulent rash of thre skin, “tanny” skin)?

Hair growth pattern:  pathological, excessive, baldness (indicate if any).

Female should be asked about first menstrual period, the duration and regularity of mensrual period, bleeding between periods or during menopause, menstrual cycle disorders, subjective senses associated with menopause (headache, depression, hot flashes). Absence of menses, sterility if any. Evaluation of libido.

 

Musculo-skeletal apparatus

 Pain in joints, bones, muskces: yes, no. If yes, define the following:

           -location; “wandering” pain if any;

           -timing, duration of pain, its intensity;

           -under what conditions does it develop or  aggravate: motion, depending on meterological factors etc.;

           -relieving factors;

           -pain in the backbone at motions (in which zones)?

           -Have the patient ever been noticed puffiness of joints or changes of their configuration, any deformations? Changes of skin above joints (reddness, glitter, tension, local rising of skin temperature (indicate the afflicted joint)?

           -Is the patient satisfyed with volume of movements in upper, lower limbs?

           -Joint and vertebral columne stiffness (location, duration, under what conditions does it develop  or aggravate, when does it disappear).

 

Nervous system and sensory organs

Does the patient feel headache? If yes, define the character, location, intensity, timing, duration of headache. What factors do relieve or remove  it?

Dizziness: when does it occure, its duration, timing, frequency, intensity.

Sleep: its deepness, duration, character of dreams (normal, deep, insomnia). Does the patient sleep well? Any unususal, expressive dreams.

Work capacity: preserved or  reduced.

Mood: its changes, excessive erritability, tearfulness, apathy, peculiarities of behavior and  speech.

Convulsions, muscular tremor, dizziness, loosing of consciousness (indicate if present). Feeling of weakness in limbs. Deranged sensitivity (parestesias and the like), disorders of gait.

Disorders of sense organs: changes of vision, hearing, smell, taste, desire to eat inedible substances. Noise in the ears if any.

 

Blood system

Pain in bones (indicate its location),  in the right or left hypochondrium: when does it occur, its character, time relationship, duration, intensity, provoking and relieving factors.

Bleeding, hemorrhagic rash on the skin and mucous membranes (their location, character, frequency of occurence, duration). Provoking and relieving factors.

Enlargement of perypheric lymph nodes if any: (their location, consistency, painfulness).

Condition of skin and mucous membranes (itching, pain, change of colour, necrotization). Enlargement of the abdomen in the projection of liver and spleen.

 

General complaints (molestia communis): rise of body temperature (indicate the time and limits of its fluctuation during a day, relieving factors); character of fever and its duration. Chills and their frequency. Sweating: its intensity and time of occurence (night sweating). General indisposition, weakness, fatigue, decreasing of work capacity, other complaints.

 

History of present illness (Anamnesis morbi)

When and  under the what conditions did the first signs of the disease appeare?

What was the beginning (onset) of the disease (acute, gradual) 

What were the first signs of the disease?

What is the main cause of the disease on the patient’s own opinion? What preceded the disease (overcooling, infection, stress, physical examination or other factors)?

Did the first symptoms change in dynamics? Did new symptoms occur from the beginning of the disease till the moment of admission? (rising, aggravation, releising or removing of new symptoms should be described in chronologic sequence).

Did the patient receive any treatment before the admission to the hospital? If yes, what was it (self-treatment, ambulatory or long-standing hospital treatment)? What kind of medicines or another therapeutical agents did the patient receive?

What was the result of previous treatment (did the patient feel him better, worse or without any  changes)?

Have the patient been ever examined before present admission to the hospital? If yes, what are the results of examination?

In the case of chronic disease following should be detalized: the first attack of the disease (its detail describtion – onset, duration, severity etc), course (frequency, duration of exacerbations, results of their treatment, patient’s self-being after treatment and during remissions),  diagnosis, that was made at previous examinations. The last exacerbation should be described literally. Data about course of the disease during present treatment in the hospital should be recorded too (till the moment of the beginning of curation).

Patient’s work-status (medical insurance) before the hospitalization is than clarified as well as  reasons of hospitalization. Dynamics of symptoms after present admitting till the moment of examination is given.

 

 Patient’s life history (Anamnesis vitae)

The main data about patient’s life should be presented in a short form.

Physical and phsychomotor development of the patient in childhood. Progress in studing process at school: what were the skills in theoretical subjects and physical training (excellent, good, bad), the interest for education and contact with school friends, hobby).

The beginning of work activity and following professional way (which professions was the patient dealt with and how long, the kind of activity (physical, mental), labor conditions, probably harmful professional factors). Present labor conditions: strong noise, vibrations, high ambient temperature, draftes, moistness, character of illumination, cold (work in the open), some chemical and radiation agents.

The mode of work activity: duration of work, breaks, holidays, leave. Are there any tensions at work? If any professional disease is suspicted professional anamnesis should be taken more detaily (see appendix 2).

Material and housing conditions in different periods of patient’s life and nowadays: what is the area of house (flat), which floor does the flat occupy, character of heating, moistness, draftes. Composition of family, family budget, any tensions in the family. How does the patient   spend his leisure time: is it enough time for sleep, rest, walks in the open. Gardening, sport (what kind of sports and exercises does he go in for).

Nutritional mode: regular or irregular feeding, frequency of meals, does the patient eat in the housing conditions or out of home. The character of meals, nutritional habits,  dry meals.

Harmful habits: smoking – if yes, indicate, in which age did the patient start to smoke, the quantity of  sigarettes smoked per day, smoking on empty stomach and at night;

-            alkohol consumption - if yes, ask about the following: in which age did the patient start to drink alkohol, how often and how much does he drink, the sort of drink, how does the patient tolerate alkohol;

-            coffeiemania - does the patient drink coffee, if yes - how often and in which day time;

-             drug abuse, toxicomania.

Any diseases, traumas, contusions, wounds in the past - if yes, enumerate all of them in chronological sequence with indication of the following: in which patient’s age did the mentioned above conditions take place, their duration, severity, complications; treatment should be indicated as well.

Special attention should be paid to infectious diseases (thyphus, hepatitis etc.) as well as to veneral diseases, AIDS, tuberculosis in the patient and his relatives. AIDS-risk factors: residence in  endemic regions, multiple sexual relations and perversions, repeated hemotransfusions, operations. If  there is suspicion on infectious disease - infectious anamnesis should be taken more detaily (see appendix 3).

 Family anamnesis:

In female patient it should include the following information:

  -when did the first menstruation (menarche) take place, character of menses (regularity, duration, volume of discharged blood). The age of marriage and beginning of sexual life. Number of  pregnancies and  their results: abortions, inevitable abortions (in which reason), miscarried fetus, delivery, premature birth, jaundice of newborns;

  -breach of menstrual function: painful, premature, delayed, protracted, excessive menstruations, bloody discharges between menstruations. Inflammation of female reproductive system organs;

  -if menstruation had disappearted (climax), it should be recorded in which patient’s age did it take place, were (are) there any unpleasant feelings during climax (headache, reddening of the face, irritability etc.).

In male patients in should be indicated the following information: breach of descent of testes (monirchodoism, cryptorchism), inflammatory diseases  of testes, prostate; sexual problems.

Allergological anamnesis:

Allergic reactions (urticaria, Quincke’s edema, anaphylactic shock etc.) to different kind of food, medicines, industrial or domestic allergens, trees’ blooming, feather etc.  Allergic diseases of relatives. Have any transfusions of blood or blood substitutes been ever given, if yes - has the patient showed  any reactions on them?

Genetic anamnesis: Can the patient remind any genetic diseases in his family? What is  the state of health or cause of death of close relatives (if somebody of relatives had died  – indicate in which age it took place). Has (had) somebody of relatives diabetes mellitus, bronchial asthma or another chronic hereditary-predisposed  diseases? Special attention should be paid for diseases with clinical manifestation similiar to these in the patient.