1. Bleeding Disorders
Meera Shreedhara
8/25/08

2. What is it?
A bleeding disorder is an acquired or inherited tendency to bleed excessively

5. Mechanisms of bleeding
Vascular Integrity
Platelets
Clotting factors
Fibrinolysis
Derangement of any of these factors can cause abnormal bleeding

6. Key to diagnosis
History

7. Bleeding history Epistaxis Gingival hemorrhage Mucosal Bleeding
Heavy Menses
Child birth
Easy bruisability
Bleeding following tooth extractions
Hematomas
Bleeding following surgery
Hemarthrosis

8. Medication History Aspirin Warfarin NSAIDS B- Lactam antibiotics
Clopidogrel and other antiplatelet agents
Herbal medications.

9. Nutritional history Vit K deficiency Vit C deficiency
Broad spectrum antibiotics

10. Clinical Characterisitc
Platelet defect
Clotting factor deficiency
Site of bleeding
Skin, mucous membranes (gingivae, nares, GI and genitourinary tracts)
Deep in soft tissues (joints, muscles)
Bleeding after minor cuts
Yes
Not usually
Petechiae
Present
Absent
Ecchymoses
Small, superficial
Large, palpable
Hemarthroses, muscle hematomas
Rare
Common
Bleeding after surgery
Immediate, mild
Delayed, severe

15. History Should the pt undergo a limited or extensive workup?
Is this acquired or hereditary?
Is this likely a disorder of clotting factors,platelets, fibrinolysis or vWF?
Do medications or intercurrent illnesses play a role?
What is the immediate cause for which a workup is being done?

16. Hereditary Deficiency of coagulation factors Platelet disorders
Hemophilia
Fibrinogen deficiency
Von Willebrand disease
Platelet disorders
Glanzmann thrombasthenia
Bernard-Soulier syndrome
Platelet granule disorders
Fibrinolytic disorders
Alpha 2 antiplasmin deficiency
PAI 1 deficiency
Structural disorders
Hemorrhagic Telangiectasias
Ehler Danlos syndrome

17. Acquired Thrombocytopenis Liver disease Renal failure Vit K deficiency
Acquired antibodies to coagulation factors
DIC
Drugs
Vascular

18. Lab testing Platelet count
Bleeding time-Measure of the interaction of platelets with the blood vessel wall.
Thrombocytopenia (platelet count usually below 50,000/microL),
Qualitative platelet abnormalities (eg, uremia),
von Willebrand disease (VWD),
Vascular purpura,
Severe fibrinogen deficiency

19. Platelet function assay
Expose platelets within citrated whole blood to high shear (5,000 to 6,000/sec) within a capillary tube and monitor the drop in flow rate as the platelets form a hemostatic plug within the center of a membrane coated with collagen and either ADP or epinephrine
Abnormal closure times are an indication of platelet dysfunction, they are not specific for any disorder
The test is coagulation factor independent
PFA-100™ is more sensitive (>70 percent) than the bleeding time (20 to 30 percent) in detecting all subtypes of von Willebrand's disease (vWD)
Exception is type 2N vWD, in which the hemostatic defect resides in the Factor VIII binding site on vWF

20. Platelet function assay
Collagen/epinephrine closure time (CEPI-CT)- Abnormal in Aspirin intake
Collagen/adenosine diphosphate (CADT-CT)-Normal in aspirin intake

21. Prothrombin time Measure of the extrinsic pathway and common pathway
Bypasses the intrinsic pathway and uses thromboplastins to substitute for platelets
Within the combined pathway, factors VII, X, and prothrombin are vitamin-K dependent and are altered by warfarin

23. Prolonged PT Vitamin K deficiency
Liver disease, which decreases the synthesis of both vitamin K-dependent and -independent clotting factors.
Deficiency or inhibition of factors VII, X, II (prothrombin), V, or fibrinogen
The infrequent antiphospholipid antibodies (lupus anticoagulant phenomenon) with antiprothrombin activity
Heparin does NOT prolong the PT

24. aPTT Measures the intrinsic and common pathways of coagulation
Uses partial thromboplastins; they are incapable of activating the extrinsic pathway
Prolonged in deficiency of, or an inhibitor to, any of the clotting factors except for factor VII
Prolonged in the presence of Lupus Anticoagulant.
Used to monitor heparin activity

27. Thrombin time
Measure conversion of fibrinogen to fibrin monomers and the formation of initial clot by thrombin
Hypofibrinogenemia,
Dysfibrinogens
Increased fibrin split products
Heparin increases TT but not RT

29. Factor deficiencies/ inhibitors
A prolonged aPTT can be due to a deficiency (or absence) of a coagulation factor or the presence of a coagulation factor inhibitor
Mixing studies help differentiate this
Lupus anticoagulants can result in a prolonged aPTT that is not correctable by the addition of normal plasma
Overcome by adding excess platelet phospholipid (particularly a hexagonal phase phospholipid) or by assessing the diluted Russell's viper venom time

30. Fibrinolysis
Fibrin and fibrinogen degradation products (FDP) are protein fragments resulting from the action of plasmin on fibrin or fibrinogen

31. Fibrinolysis
FDP assays do not differentiate between fibrin degradation products and fibrinogen degradation products
Fibrin D-dimers are degradation products of cross-linked fibrin
D-dimers specifically reflect fibrinolysis of cross-linked fibrin (ie, the fibrin clot) – so are more reliable indicators of thrombosis

32. Fibrinolysis Assays for plasminogen,
Tissue plasminogen activator (t-PA),
Alpha-2 antiplasmin,
Plasminogen activator inhibitor-1 (PAI-1),
Thrombin-activatable fibrinolysis inhibitor (TAFI).

33. Normal PT and PTT Thrombocytopenia vWD Factor 13 deficiency
Platelet dysfunction
Vascular purpuras
Psychogenic purpura

34. Normal PT and Prolonged aPTT
Hemophilia A
Hemophilia B
Factor XI deficiency
Factor VIII inhibitor
Malignancy,
Clonal lymphoproliferative disorders,
Pregnancy,
Rheumatologic disorders

35. Prolonged PT and normal aPTT
Factor VII deficiency
Warfarin therapy
Early liver disease
Early DIC

36. Prolonged PT and PTT Vit K deficiency Liver disease Warfarin treatment
Acquired inhibitor to factor V
Factor X deficiency- seen in Amyloidosis
DIC

37. Acute Promyelocytic Leukemia
DIC is often seen at presentation or during treatment
Medical Emergency as Cerebral hemorrhage can occur in upto 4% of untreated pts
Promyelocytes seen on smear
Reciprocal translocation between the long arms of chromosomes 15 and 17, with the creation of a fusion gene, PML/RAR-alpha
Immediate initiation of ATRA induces de deifferentiation

38. Hemophilia Hemophilia A and B are X-linked recessive diseases
Severe disease <1 % factor activity,
Moderate disease- 1 to 5 %
Mild disease >5 %
The most common sites are into joints and muscles and from the gastrointestinal tract

39. Treatment
The two components to therapy are treatment of active bleeding and inhibitor ablation via immune tolerance induction
Cryoprecipitate has high levels of factor VIII
Porcine Factor VIII
Recombinant human Factor VIII
The choice of factor VIII product usually is based upon safety, purity, and cost.

40. Dosing
One international unit (IU) of clotting factor is that amount present in 1 mL of pooled normal plasma
Dose of F VIII (IU) = Weight (kg) x (Desired % increase) x 0.5
Depends on the clinical indication and the presence of inhibitors

41. von Willebrand’s disease
Most common of the inherited bleeding disorders
In 1926, Erik von Willebrand described the first patient with the disease
Von Willebrand factor (VWF) binds to both platelets and endothelial components, forming an adhesive bridge between platelets and vascular subendothelial structures and between adjacent platelets at sites of endothelial injury

42. Acquired von Willebrand’s disease
Malignant diseases
Monoclonal gammopathy of unknown significance
Multiple Myeloma
Non-Hodgkin's lymphoma
Chronic lymphocytic leukemia
Waldenstrom's macroglobulinemia
Essential thrombocythemiaPolycythemia vera
Chronic myelogenous leukemia
Wilms tumor
Other carcinomas
Immunologic disorders
Systemic lupus erythematosus
Other autoimmune diseases
Other disorders
Hypothyroidism
Ventricular septal defect
Aortic stenosis
Mitral valve prolapse
Gastrointestinal angiodyplasia
Uremia
Hemoglobinopathies
Drugs and other agents
Valproic acid
Antibiotics

43. Treatment DDAVP Replacement of vWF EACA Tranexamic acid
Recombinant factor 7

44. Its better to bleed than clot!

45. Therapies other than factor replacement
DDAVP
EACA
Tranexamic Acid
Factor 7 inhibitor- Novoseven

46. Liver disease Vs DIC
Low factor V levels can be used as evidence for either reduced hepatic synthetic function or increased consumption, as in DIC
Factor VIII is not manufactured by hepatocytes; factor VIII levels are usually normal or increased in liver disease