Coagulation Disorders

1. Coagulation Disorders Assistant Professor Dr Talib Hussein Kamoona (CABM) Hematologist/Medical Oncologist

2. Hemostasis * The intimal surface of blood vessels throughout the body is lined by monolayer of endothelial cells. These express anticoagulant properties that promote blood fluidity normally. At the site of vascular injury endothelial cells are activated and converted from antithrombotic to prothrombotic state or become detached exposing circulating blood to thrombogenic constituents of subendothelium.

3. This results in platelet adhesion that is mediated by vWF that anchors platelets to blood vessel wall by binding to platelet GPIb receptors. Then adherent platelets undergo "release" reaction discharging constituents of their storage granules such as ADP, TXA2 which causes further platelets adhesion & platelet activation. Activated platelets expose binding sites for fibrin (GP IIb-IIIa), and then fibrin is formed from plasma fibrinogen by the action of thrombin. This results from the activation of coagulation factors cascade b y either the intrinsic or extrinsic pathways.

4. Coagulation Cascade

5. A 10-year-old Caucasian male is to undergo an elective tonsillectomy. The pre-operative history describes significant bleeding after a recent tooth extraction. The mother reports that the bleeding occurred several hours after the tooth extraction, after they had returned home from the dentist’s office.

6. What additional questions regarding the patient’s history would be important to determine if the patient has an underlying coagulopathy? * Is there a history of bleeding after surgery or injuries? * Does the patient suffer from recurrent infections? * Was he taking any medication at the time of his dental extraction, and is he taking any now? * Is there a family history of bleeding disorders? * Is there a history of significant weight loss?

7. * Evaluation of prior bleeding has been shown to be predictive of a bleeding disorder. Evaluation of a patient’s history should focus on spontaneous bleeding, bleeding after trauma and surgical procedures, and in women, the presence of menorrhagia. * Someone who does not have bleeding complications after trauma or surgical challenges is less likely to have a significant coagulation disorder. * Disorders of platelet function or number tend to produce immediate bleeding after surgical procedures or trauma, in contrast to disorders of the coagulation system, which may present as delayed bleeding after initial hemostasis was obtained.

8. * Family history, when positive, is also strongly associated with inherited bleeding disorders, although genetic coagulation disorders may also arise from spontaneous gene mutations. * Since there are many medications that increase the risk of bleeding, one should take a history of all prescribed and over-the-counter medications.

9. * Family history, when positive, is also strongly associated with inherited bleeding disorders, although genetic coagulation disorders may also arise from spontaneous gene mutations. * Since there are many medications that increase the risk of bleeding, one should take a history of all prescribed and over-the-counter medications. * Family history, when positive, is also strongly associated with inherited bleeding disorders, although genetic coagulation disorders may also arise from spontaneous gene mutations. Since there are many medications that increase the risk of bleeding, one should take a history of all prescribed and over-the-counter medications.

10. What aspects of the physical exam do you think would be most relevant in this case? * Skin * Eyes * Lymph nodes * Abdomen * Joints

11. Which of the following tests should be ordered to help in the initial evaluation of this patient? * Complete blood count with differential and evaluation of blood smear * Prothrombin time (PT) and partial thromboplastin time (PTT) with mixing studies * Bleeding time * Measurement of von Willebrand activity and antigen level

12. Laboratory Test Results

13. Given these laboratory results, which of the following are possible diagnoses in this patient? * Von Willebrand disease * Hemophilia A * Hemophilia B * Glanzmann’sthrombasthenia * Platelet storage pool disorder

14. What factor(s) would you test to diagnose this disorder? * Factor VIII * Factor IX * Factor XI * Factor XII

15. TEACHING POINTS 1. A history of bleeding after previous surgical procedures or trauma suggests a relatively high likelihood of an underlying coagulation disorder. 2. It is important to obtain a complete family history, which may alert you to an inherited coagulation disorder such as hemophilia A or von Willebrand disease. 3. The laboratory evaluation of a patient with a suspected bleeding disorder should be directed by the findings of the history as well as the physical examination. An evaluation of the PT, the PTT and the complete blood count are typically a common starting point to evaluate the etiology of a patient’s bleeding symptoms.

16. TEACHING POINTS 4. Patients with a diagnosis of hemophilia A will typically have findings and symptoms that are directly related to the level of factor VIII activity. Patients with less than 5% of factor VIII activity are more likely to have spontaneous bleeds into joints (hemarthroses), while less severely affected patients with higher (but still abnormally low) factor VIII levels may have bleeding symptoms only after trauma or surgical procedures. 5. There are other causes of prolonged PTT besides hemophilia A and B. These include hemophilia C (factor XI deficiency) and factor XII deficiency. Factors XII and XI are typically evaluated only if factors VIII and IX are normal.

17. Hemophilias Hemophilia A (HA), considered the classic form of the disease, results from a congenital deficiency of factor VIII (FVIII). Hemophilia B (HB), also called Christmas disease, is a consequence of a congenital deficiency of factor IX (FIX) Hemophilia C (deficiency of factor XI)can be distinguished from hemophilia A (deficiency of factor VIII) and hemophilia B (deficiency of factor IX) by the absence of bleeding into joints and muscles and by its occurrence in individuals of either sex. autosomal but not completely recessive because heterozygotes may have bleeding.

18. Genetics X-linked recessive --- Genes located on long arm of X-chromosome --- Usually affects males --- Females are carriers transmitting disease to sons --- Female hemophiliacs may be seen in: * X-chromosome lyonization * mating between hemophiliac male & female carrier * Carrier female with Turner's syndrome * Carrier with testicular feminization

19. S&S --- Severity of bleeding related to level of plasma FVIII * < 1% activity --- severe disease * 1-5% activity --- moderate clinical course --- bleeding in severe cases in early infancy during circumcision or even during intrauterine life --- Spontaneous bleeding --- Acute hemarthrosescausing burning or tingling sensation followed by intense pain & swelling. The joint is swollen, hot & tender with erythema of the overlying skin. Joint stiffness & compromised mobility & maintained in a flexed position * Joint aspiration is not recommended because it may introduce infection * FVIII replacement rapidly stops bleeding, resolves hematoma & improves symptoms

20. * Recurrent hemarthroses result in chronic synovial hypertrophy, damage to cartilage, subchondral bone cyst formation, bony erosion & flexion contractures. Later OA changes * Dx by MRI & ultrasound since x-ray may underestimate the extent of bone & cartilage damage * Analgesics, rest, avoidance of wt bearing, avoid NSAIDs * Synovectomy surgical & non-surgical * Non-weight bearing exercises * Joint prosthesis or arthrodesis * Prevention – planned administration of FVIII 3 times per week at levels to maintain factor activity at 1-2% normal

21. --- Intramuscularhematomas * follow trauma or IM injection or vaccination * may compress vital structures --- Retroperitoneal hematomas * should be treated aggressively & immediately --- Mucosal hemorrhage may be seen nose, GIT, GUT --- Intracranial bleeding 2nd cause of death after AIDS

22. Ask about the patient's family history and bleeding symptoms. Male patients with severe hemophilia present at circumcision. Easy bruising may occur at the start of ambulation or primary dentition. The patient may have a history of hemarthroses and prolonged bleeding with surgical procedures, trauma, dental extraction, and he or she may have spontaneous bleeding in soft tissues. A traumatic challenge relatively late in life may have to occur before mild or moderate hemophilia is diagnosed. Factors that elevate FVIII levels (e.g. stress, exercise) may mask mild hemophilia. Physiologically low levels of all vitamin K–dependent procoagulant factors may complicate the early diagnosis of hemophilia B.

23. The principal sites of bleeding in patients with hemophilia are as follows: For joints, weight-bearing joints and other joints are affected. Regarding muscles, those most commonly affected are the flexor groups of the arms and gastrocnemius of the legs. Iliopsoas bleeding is dangerous because of the large volumes of blood loss and because of compression of the femoral nerve. In the genitourinary tract, gross hematuria may occur in as many as 90% of patients. In the GI tract, bleeding may complicate common GI disorders. Bleeding in the CNS is the leading cause of hemorrhagic death among patients with hemophilia

24. Physical Exam Direct the examination to identify signs related to spontaneous or, with minimal challenge, bleeding in the joints, muscles, and other soft tissues. Observe the patient's stature. Examine the weight-bearing joints, especially the knees and ankles, and, in general, the large joints for deformities or ankylosis. Look for jaundice, other signs of liver failure (eg, cirrhosis from viral infection), and signs of opportunistic infections in patients who are HIV seroconverted

25. Laboratory Studies The plasma concentration of FVIII or FIX determines the severity of hemophilia. Levels of these factors are assayed against a normal pooled-plasma standard, which is designated as having 100% activity or the equivalent of FVIII or FIX 1 U/mL. Patients' tested values ranging from 50-150% are considered in the normal range of variance. Aging, pregnancy, contraceptives, and estrogen replacement therapies are associated with increased levels. In term and healthy premature neonates, FIX values are lowered (20-50% of the normal level) and rise to normal levels after 6 months (hepatic immaturity). FVIII levels are normal during that period of life. Spontaneous bleeding complications are severe in individuals with undetectable activity (<0.01 U/mL), moderate in individuals with activity (2-5% normal), and mild in individuals with factor levels greater than 5%. ).

26. Hemophilia A and hemophilia B protein deficiencies of the intrinsic pathway result in abnormal whole-blood clotting times, prothrombin times (PTs), and activated partial thromboplastin times (aPTTs). FVIII and FIX activities are usually determined by using the 1-stage assay based on the aPTT.

27. Differentiation of hemophilia A from von Willebrand disease is possible by observing normal or elevated levels of von Willebrand factor antigen and ristocetin cofactor activity. Bleeding time is prolonged in patients with von Willebrand disease but normal in patients with hemophilia. Laboratory confirmation of a FVIII or FIX inhibitor is clinically important when bleeding is not controlled after adequate amounts of factor concentrate are infused during a bleeding episode. For autoantibody and alloantibody inhibitors, obtain a repeat measurement of the patient's prolonged aPTT after incubating the patient's plasma with normal plasma at 37°C for 1-2 hours. If the prolonged aPTT is not corrected, use the Bethesda method to titrate the inhibitor biologic concentration. By convention, more than 0.6 BU is considered a positive result for an inhibitor, less than 5 BU is considered a low titer of inhibitor, and more than 10 BU is a high titer (neutralizing effectiveness of factor concentrate therapy to control bleeding )

28. ℞ --- FVIII replacement * Severe cases need 50000-80000 IU per year Level 80-100% for surgery & life threatening bleeds 50% for serious bleeds 25-30% for minor bleeds (hemarthroses & hematuria) 1 IU FVIII / kg body wt = 2% activity increase 3500 IU for 70 kg adult with severe disease needs 100% level Subsequent dosing every 8-12 hours up to 10-14 days --- Cryoppt is a rich source of FVIII --- FFP --- HB vaccination at an early age --- HA vaccination --- Ancillary ttt * Anti fibrinolytic agents – EACA, tranexamic acid * DDAVP intravenously or intra nasally

29. Prevention Prophylactic replacement of FVIII or FIX is used to maintain a measurable level at all times, with the goal of avoiding hemarthrosis and breaking the vicious cycle of repetitive bleeding and inflammation that results in destructive arthritis. This goal is achieved by administering factor 2-3 times a week. The National Hemophilia Foundation has recommended the administration of primary prophylaxis, beginning at the age of 1-2 years. Carrier testing may prevent births of individuals with major hemophilia. This testing can be offered to women interested in childbearing who have a family history of hemophilia. Carrier testing is valuable for women who are related to obligate carrier females or males with hemophilia. Prenatal diagnosis is important even if termination of the pregnancy is not desired because a cesarean delivery may be planned or replacement therapy can be scheduled for the perinatal period.

30. Disseminated intravascular coagulation (DIC)

31. (defibrination syndrome) It is a consumptive coagulopathy that is caused by a wide variety of serious disorders.

32. Etiology * Infections --- G-ve bacterial sepsis --- Other bacteria, fungi, Rocky Mountain spotted fever, viruses, malaria

33. Obstetric complications --- Amniotic fluid embolism --- Retained dead fetus --- Abruptioplacentae --- Toxemia of pregnancy --- Septic abortion

34. Malignancies ---- Pancreatic Ca --- Adenocarcinomas --- Acute promyelocytic leukemia (M3) --- Other neoplasms

35. Trauma ---- Shock --- Brain injury --- Crush injury --- Burns --- Hypothermia/ Hyperthermia --- Fat embolism, ischemia, hypoxia --- Surgery

36. Vascular disorders --- Giant hemangiomas (Kassabach-Merritt syndrome) --- Vascular tumors, Aortic aneurysms

37. OTHERS * Liver failure * Acute pancreatitis * Snake venom * ARDS * Blood transfusion reaction

38. Pathogenesis It is primarily a thrombotic process although its clinical manifestations may be widespread hemorrhage. The basic trigger irrespective of etiology is entry into the circulation of procoagulant substances activating coagulation factors & platelets leading to disseminated deposition of fibrin-platelet thrombi. In most cases the procoagulant stimulant is tissue factor (a lipoprotein that is not normally exposed to blood), mucin in certain malignancies, proteases in other malignancies, pancreatitis, and envenomation.

39. S&S Asymptomatic --- low grade DIC showing only Lab abnormalities

40. Thrombotic complications --- Trousseau's syndrome --- Gangrene of digits & extremities --- Hemorrhagic necrosis of skin --- Purpura fulminans

41. Bleeding --- most common manifestation in acute cases --- Generalized & widespread --- Characteristically from the cannula site --- oozes from mucosal surfaces & orifices Clinical manifestations of the causative disease

42. Dx PT, aPTT & TT are prolonged Thrombocytopenia, Plasma Fibrinogen ↓ FDPs ↑ (measured by latex agglutination or D-dimer assay) Blood film --- Schistocytes, fragmented RBCs

43. ℞ Identify & correct the cause No treatment --- asymptomatic cases (not ttt lab manifestations) Hemodynamic support Blood component therapy --- FFP, platelets, cryoppt Drugs --- Inhibitors of coagulation & fibrinolysis Heparin – theoretic benefit (if thrombosis predominates) -- may exacerbate bleeding Antifibrinolytics – EACA & tranexamic acid -- Generally C/I in DIC -- may be useful in life-threatening bleeding

47. Platelet Disorders

48. Thrombocytopenia It is a condition in which platelet count is below normal level.

49. Causes 1- Aplastic anemia. 2- Leukemia. 3- Tumors metastatic to BM. 4- Myelofibrosis. 5- Megaloblastic anemia. 6- Peripheral platelet destruction a- Immune ITP, SLE, PAN, CLL, NHL, infectious mono, CMV infection, HIV, quinine, quinidine, heparin & sulfa. b- Non-immune DIC, TTP, PNH, acute transplant rejection. 7- Disorders of distribution--- Hypersplenism. 8- Dilutional --- Old banked blood transfusion.

50. Idiopathic Thrombocytopenic Purpura: (ITP) It is a bleeding disorder caused by autoimmune Abs destroying patient's own platelets by phagocytosis in the spleen by Mφ (to a lesser degree in the liver).