Bleeding and Platelet Disorders

Question 1

Causes of Thrombocytopenia

Answer 1

• decreased production
• increase use or destruction
  
  • Immune
  • Increased clotting (DIC)
  • Microangiopathy (TTP, HUS)
• sequestration

Question 2

Clinical presentation of Thrombocytopenia

Answer 2

• Petechiae (suggests platelet defect)
• Ecchymopsis (bruise) (suggests clotting factor def.)
• Hematoma (suggests clotting factor def.)

Question 3

Immune Thrombocytopenic Purpura (ITP)

Answer 3

• an autoimmune disorder characterized by development of IgG antibodies against the GPIIb/IIIa receptor
• diagnosis made by excluding other options
• Adult form: more autoimmune disorder; chronic, reccuring
• Child form: self-limited, often follows a viral infection; Ab interacting with virus; can be eliminated
• history of easy bruising, epistaxis, gingival hemorrhage, menorrhagia, and soft tissue hemorrhage from minor trauma
• Lab: thrombocytopenia, normal PT and PTT
• treatment: corticosteroids, IVIG, splenectomy, thrombopoietic drugs (though cause marrow fibrosis)

Question 4

Drug-Induced Thrombocytopenia

Answer 4

• drug-induced immune complex
• Severe, sudden onset
• example drugs: quinine, quinidine, sulfa drugs, rifampin; heparin (different mechanism)
• treatment: remove drug, could use non-heparin anticoagulant if problem is from heparin

Question 5

Platelet Transfusion

Answer 5

• Used in treating thrombocytopenia due to marrow failure
• Common in cardiac surgery, liver transplant
• Transfused platelets only survive 2-3 days (Short survival in consumptive thrombocytopenia)

Question 6

Inherited Disorders that affect primary hemostasis

Answer 6

Bernard-Soulier: platelets lack von Willebrand factor receptor (GP Ib), unable to adhere. Platelet count usually low

Glanzmann’s Thrombasthenia: platelets lack fibrinogen receptor (GP IIb/IIIa), unable to aggregate

von Willebrand Factor: deficiency of vWF

Question 7

causes of platelet dysfunction

Answer 7

• inherited disorders
• drugs (aspirin, clopidigrel, IIb/IIIa receptor antagonists)
• uremia
• monoclonal gammopathy (myeloma)
• myeloproliferative disorders

Question 8

von Willebrand Disease

Answer 8

• Common
• Mild/moderate bleeding; enough to have pt come to clinic, but not severe
• Deficiency of VWF; factor VIII also low
• Autosomal dominant with varied penetrance (same genotype doesn’t equal same phenotype)
• Lab FindingsSubnormal levels of von Willebrand factor and (typically) factor VIII in plasma
• Some VWD variants disproportionately affect VWF activity - protein level can be near-normal
• Defective platelet adherence (PFA-100)
• PTT may be prolonged if factor VIII level low enough (≤ 30%)

Question 9

Glanzmann’s thrombasthenia

Answer 9

• bleeding disorder caused by genetic deficiency of GPIIb/IIIa. It results in a decreased ability to facilitate platelet aggregation
• Blood smear in patients with Glanzmann thrombasthenia shows no platelet aggregation
• significant mucocutaneous bleeding and a normal platelet count but with single isolated platelets without any platelet clumping on examination of a non-anticoagulated peripheral blood smear should raise the possibility of this disorder
• PT/INR and aPTT, Thrombin time going to be normal - anything that measures coagulation will be normal because the IIb/IIIa receptor deficiency doesn’t affect coagulation.

Question 10

Bernard-Soulier syndrome

Answer 10

• platelets lack von Willebrand factor receptor (GP Ib), unable to adhere. Platelet count usually low
• giant platelets, and bleeding that is greater than expected for the degree of thrombocytopenia
• can be tested for with Ristocetin assay; wouldn’t get clotting in ristocetin test

Question 11

In clotting deficiency, level below ____ of normal of single factor associated with increased bleeding risk

Answer 11

~ 30%

Question 12

genetic inheritance of most clotting factors are ____ and the exception is _____

Answer 12

most are autosomal recessive; VIII and IX are sex-linked

Question 13

Hemophila A and B deficiency in which clotting factors

Answer 13

Hemophilia A: VIII

Hemophilia B: IX

Question 14

genetics of hemophila

Answer 14

sex-linked (seen in male patients; history of sons have it); ~20% of cases are from a new mutation (not familial)

Question 15

hemophilia presentation, lab, treatment

Answer 15

• Joints and muscles most common bleeding sites
• Repeated bleeds cause permanent joint damage

LAB FINDINGS in Hemophilia

• Long aPTT, normal PT/INR
• Long aPTT corrects upon mix with normal plasma
• Low level of factor VIII or IX activity (0-30%)

Treatment: replace missing factor (recombinant proteins available)

Question 16

types of acquired clotting deficiencies

Answer 16

• vitamin k deficiency
• liver disease
• autoimmune to single factor (usually VIII)
• DIC

Question 17

Causes of Vitamin K deficiency

Answer 17

• Inadequate supply – hemorrhagic disease of newborn; hospitalized patient not eating/ on antibiotics
• Poor absorption – biliary obstruction; generalized malabsorption (celiac dz, crohn’s dz, resection of small bowel)
• Vitamin K inhibitors – warfarin

Question 18

Lab Findings of Vitamin K deficiency

Answer 18

Laboratory Findings

• Long PT/INR and aPTT
• PT/INR more sensitive (aPTT might by normal in mild cases)
• Long clotting times correct upon mix with normal plasma
• Low blood levels of vitamin K dependent factors; other factor levels are normal

Question 19

coagulation inhibitors types

Answer 19

antibodies to clotting factors

• Usually to Factor VIII
• Hemophilia (alloimmune): blocks therapeutic effect of clotting factor infusion
• Other (autoimmune): may cause severe bleeding (“acquired hemophilia”)

drugs

• Heparin and related drugs: accelerate inhibition of thrombin and/or Xa by antithrombin
• Direct thrombin and Xa inhibitors (argatroban, dabigatran, rivaroxaban, apixaban etc)

lupus anticoagulant

• binds to phospholipid and prevents catalysis of clotting cascade
• Anticoagulant effect in vitro only; does not cause bleeding, can promote thrombosis by uncertain mechanism

Question 20

lab findings in coagulation inhibitors

Answer 20

• Prolonged Clotting Time that does not correct by mixing study (addition of normal plasma)
• Heparin: aPTT (used to monitor drug), thrombin time (most sensitive), PT/INR at high levels
• Factor VIII inhibitors: aPTT only
• Lupus anticoagulant: aPTT, occasionally PT/INR

Question 21

Disseminated Intravascular Coagulation (DIC) - pathophysiology

Answer 21

• Uncontrolled, disorganized activation of clotting and fibrinolytic systems with rapid formation and lysis of intravascular fibrin
• Usually due to exposure of blood to excessive tissue factor
• Consumption of clotting and fibrinolytic enzymes and inhibitors, platelets
• Often associated with diffuse endothelial injury

Question 22

Disseminated Intravascular Coagulation (DIC) clinical presentation

Answer 22

• a systemic process of both thrombosis and hemorrhage that occurs as a result of underlying illness
• The most common etiologies of DIC include:Sepsis - bacterial lipopolysaccharides activate coagulation
• Purpura Fulminans – tissue necrosis and multiple organ failure, most often seen in severe sepsis; contributing factors are tissue hypoperfusion, endothelial injury, intravascular fibrin formation
• Trauma, especially to the central nervous system
• Malignancy - “cancer procoagulant” is produced by some mucinous tumors & can activate factor X
• Obstetrical complications such as preeclampsia, retained dead fetus, or acute fatty liver of pregnancy
• Severe intravascular hemolysis, for example, an acute hemolytic transfusion reaction or severe malaria

Question 23

Disseminated Intravascular Coagulation (DIC) Lab Findings and Treatment

Answer 23

Lab Findings

• Thrombocytopenia
• Long PT/INR
• Long PTT
• Elevated D-dimer and FDPs (FKR suggest increased fibrinolysis)
• Low fibrinogen
• FKR: Could have schistocytes
• FKR: Decreased fibrinogen, increased aPTT and PT suggest increased thrombin production

Treatment: most important is to control underlying disease

Question 24

Thrombotic Thrombocytopenic Purpura (TTP)

Answer 24

• Characterized by thrombocytopenia and microangiopathic hemolytic anemia
• Autoimmune destruction of ADAMTS13 leads to platelets clumped by unusually large von Willebrand factor multimers (ADAMTS13 would usually cut these); widespread formation of platelet aggregates in small vessels
• Organ dysfunction

Lab Findings

• Blood smear: schistocytes, absence of platelets
• Thrombocytopenia, anemia
• Intravascular hemolysis (high LDH, low haptoglobin, etc)
• Renal dysfunction (increased creatinine, proteinuria, hematuria)
• Minimal consumption of fibrinogen and other clotting factors (compared to DIC)
• Very low (<5%) ADAMTS-13 activity with circulating inhibitor
• Increased bleeding time
• Normal PT/INR and PTT

Treatment

• High mortality if untreated (>90%)
• Plasma exchange can be lifesaving’ plasmapharesis
• Replaces ADAMTS13 and removes autoantibody
• Concomitant immunosuppressive therapy often given; corticosteroids
• Mortality less than 20% if disease promptly diagnosed and appropriately treated

Question 25

Hemolytic Uremic Syndrome

Answer 25

• Characterized by microangiopathic hemolytic anemia and thrombocytopenia
• Acute renal failure is predominant feature
• Often associated with GI prodrome due to infection with toxin producing E. coli (bacterial toxin injures endothelium, causing microangiopathy and renal failure)
• Often self-limited, but susceptible patients (esp children, elderly) may have life-threatening disease
• Sporadic HUS not associated with infection often associated with inherited defects in complement regulation (“Atypical HUS”)

Lab Findings

• Blood smear: schistocytes, absence of platelets
• Thrombocytopenia, anemia
• Intravascular hemolysis (high LDH, low haptoglobin, etc)
• Renal dysfunction (increased creatinine, proteinuria, hematuria)
• Minimal consumption of fibrinogen and other clotting factors (compared to DIC)
• Very low (<5%) ADAMTS-13 activity with circulating inhibitor
• Increased bleeding time
• Normal PT/INR and PTT