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Department of
Hematology and
Medical Oncology

Department of
Hematology and
Medical Oncology

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Spontaneous, or excessive post-traumatic (immediate or delayed) bleeding may be an indication of a localized pathological process or a disorder of the hemostatic process.

Accurate diagnosis and treatment of patients with bleeding requires some basic understanding of the pathophysiology of hemostasis. The process is divided into primary and secondary components. Primary hemostasis is formation of platelet plug at sites of injury and occurs within seconds of injury. Secondary hemostasis describes the coagulation system, which result in fibrin formation. It requires several minutes to complete. The fibrin strands strengthen the hemostatic platelet plug. This process is particularly important in bleeding originating from large vessels and in preventing recurrent bleeding hours or days after the initial injury (Figure 1).

Bleeding disorders can thus be categorized into three groups: disorders of platelet function or number, disorders of clotting factors, and a combination of the above. A focused history, physical examination and screening laboratory tests are of paramount importance in directing the evaluation in a time saving and cost effective manner.

History and
Physical
Examination

Laboratory
Investigations

References

The evaluation of the bleeding patient should primarily be focused on the following:

• Is the patient bleeding? Surrogate markers of bleeding (such as a declining hemoglobin) are often subject to misinterpretation. Hence deciding whether the patient is bleeding or not should not be solely based on a declining hemoglobin or sudden hypotension. Hemolysis or hemodilution represent other causes of a decline in hemoglobin.¹
• If bleeding is suspected; identify the site and severity, duration of bleeding and clinical setting.
  • Mucocutaneous bleeding suggests a platelet disorder. It includes petechiae, ecchymoses, epistaxis, and genitourinary and gastrointestinal bleeding.
  • Bleeding into potential spaces (joints, fascial planes, retroperitoneum) suggests a coagulation factor deficiency.
  • Bleeding from multiple sites in hospitalized patients can be seen with disseminated intravascular coagulation (DIC) or Thrombotic Thrombocytopenic Purpura (TTP).

A complete history should include the following elements:^1,2

• A history of human immunodeficiency virus (HIV), liver or kidney disease, or malabsorption is often helpful.
• A medication history with particular attention to anticoagulants, nonsteroidal anti-inflammatory drugs (NSAIDs), oral contraceptives, antibiotics, ethanol, and dietary vitamin K and vitamin C.¹
• The response to past hemostatic challenge such as trauma, tooth extraction, pregnancy, surgery, sports, and menstruation.
• A family history for bleeding disorders may be helpful for the assessment of pathologic bleeding.
• The clinical setting of the bleeding patient:¹
  • Acute massive mucocutaneous bleeding in an individual previously without symptoms should suggest immune thrombocytopenic purpura (ITP).
  • Massive bruising and oozing from multiple sites in otherwise asymptomatic individuals could suggest accidental warfarin ingestion, or acquired factor VIII inhibitors (particularly in older individuals).
  • Postoperative bleeding at a surgical site is usually related to a local surgical problem.

Physical examination should focus on identifying signs of bleeding (petechiae, mucosal bleeding, soft tissue bleeding and ecchymoses) as well as signs of systemic disease.^1-3

Initial laboratory investigations should include a complete blood cell (CBC) count, prothrombin time (PT), partial thromboplastin time (PTT), and a peripheral smear. A preoperative screen for a patient with a negative history and examination should include a CBC, PT, and activated partial thromboplastin time (aPTT) only.^2,4,5 The following is a brief description of commonly obtained tests in the evaluation of hemorrhagic disorders.

• Platelet count: always verify thrombocytopenia by reviewing a peripheral smear. For example platelet clumping with ethylenediamine tetra-acetic acid (EDTA) does not represent true thrombocytopenia and an accurate platelet count can be obtained by using citrated tubes.^2,4,5
• The partial thromboplastin time (PTT): It represents the time for clot formation after adding calcium, phospholipids, and kaolin to citrated blood. It is prolonged by heparin, direct thrombin inhibitors, a deficiency or inhibitor for factors in the intrinsic and common pathway (namely, factors II, V, VIII, IX, X, XI, XII) as well as lupus anticoagulant, vitamin K deficiency, or severe liver disease.^2,4,5
• The prothrombin time (PT): It represents the time for clot formation after the addition of thromboplastin (tissue factor) and calcium to citrated blood. It is prolonged with deficiencies of factors II, V, VII, X or fibrinogen; liver disease; vitamin K deficiency and Warfarin use. The International Sensitivity Index is a measure of thromboplastin sensitivity.^2,4,5 Table 1 illustrates causes of a prolonged PT, PTT or both.
• Thrombin time (TT): time to clot formation after the addition of thrombin to citrated blood. The TT is prolonged by heparin, direct thrombin inhibitors, fibrin degradation products (FDPs), paraproteins, and fibrinogen deficiency (both qualitative and quantitative). Addition of protamine to neutralize the heparin is done to interpret the TT without heparin interference. It is used to establish the presence of adequate fibrinogen and is falling out of favor for a fibrinogen assay.^2,4,5
• Reptilase time: measures the time to clot formation after the addition of reptilase (a thrombin-like snake enzyme) to citrated blood. Unlike the TT, it is not affected by heparin. It can useful to determine if heparin is the cause of the prolonged TT.^2,4,5
• A 1:1 mixing study is done when the PT or PTT is prolonged. The patient's plasma is mixed with normal plasma and the abnormal test is repeated. If the mixing of normal plasma corrects the abnormal test (PT or PTT), then a factor deficiency is suggested; otherwise, an inhibitor is suspected. Similarly, an incubated mixing study is done 1 hour (and occasionally 2 hours) after mixing of the patient plasma with normal plasma. It is used to differentiate a Lupus anticoagulant from factor inhibitors.^2,4,5
• Urea clot solubility reflects the ability of 5 M urea to solubilize clots. Normal clots are not solubilized by urea or monochloracetic acid, but patients with factor XIII deficiency have clots that dissolve in 5 M urea.^2,4,5
• FDPs are fragments resulting from the action of plasmin on fibrin or fibrinogen and reflect high fibrinolysis states (such as DIC) when they are elevated.^2,4,5
• D-dimers are FDPs that can be measured specifically by enzyme-linked immunosorbent assay. They are commonly elevated in DIC and in thrombotic conditions such as deep venous thrombosis and pulmonary embolisms.^2,4,5 Their elevation in the absence of symptoms does not imply the presence of these disorders.
• Platelet function screen: The PFA-100 is a platelet function analyzer that is slowly supplanting the bleeding time in the clinical arena. It tests the ability of platelets to aggregate in two cartridges (collagen/ADP and collagen/Epinephrine).^6,7 It has a reported sensitivity of around 95% and specificity of around 89% in detecting platelet dysfunction and a 98% positive predictive value to detect aspirin induced platelet defects.^6,7
• Platelet aggregation study: they remain the gold standard in detecting platelet function defects. In this test, platelet aggregation in response to a variety of agents is tested including: ADP, epinephrine, collagen, Arachidonic acid, and Ristocetin. Platelets of patients with Glanzmann's Thrombasthenia only aggregate with Ristocetin, while platelets of patients with Bernard Soullier syndrome have absent aggregation with Ristocetin, reduced aggregation with collagen and normal aggregation with ADP, Arachidonic acid and epinephrine.⁴
• Von Willebrand screen includes tests of platelet function. It has a low negative predictive value and may require repeat testing. It includes the following tests:^2,4,5,8

1. Von Willebrand factor antigen (vWF:Ag): immunoassay for circulating vWF.Von Willebrand factor activity (vWF:RCo): measures the functional ability of a patient's vWF to agglutinate platelets in the presence of Ristocetin.
2. Factor VIII:C activity: is functional assay for factor VIII. It is measured by mixing normal plasma with factor VIII-deficient plasma.

• vWF:Ag and vWF:RCo may be elevated during pregnancy, oral contraceptive use, and liver disease. They are decreased by hypothyroidism and type O blood. Table 2 illustrates the use of these tests for the diagnosis of von Willebrand disease.⁴

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1. Kitchens CS. Approach to the bleeding patient. Hematol Oncol Clin North Am. 1992;6:983-989.
   
   
2. Sallah S, Kato G. Evaluation of bleeding disorders. A detailed history and laboratory tests provide clues. Postgraduate Medicine. 1998;103:209-210.
   
   
3. Rosen PJ. Bleeding problems in the cancer patient. Hematol Oncol Clin North Am. 1992;6:1315-1328.
   
   
4. Kottke-Marchant K. Laboratory diagnosis of hemorrhagic and thrombotic disorders. Hematol Oncol Clin North Am. 1994;8:809-853.
   
   
5. Redei I, Rubin RN. Techniques for evaluating the cause of bleeding in the ICU. Diagnostic clues and keys to interpreting hemostatic tests. J Crit Illn. 1995;10:133-137.
   
   
6. Mammen EF, Comp PC, Gosselin R, et al. PFA-100 system: a new method for assessment of platelet dysfunction. Semin Thromb Hemost. 1998;24:195-202.
   
   
7. Jilma B. Platelet function analyzer (PFA-100): a tool to quantify congenital or acquired platelet dysfunction. J Lab Clin Med. 2001;138:152-163.
   
   
8. Bick RL. Acquired platelet function defects. Hematol Oncol Clin North Am. 1992;6:1203-1228.

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