Coagulation Defects and Disease States

Two Broad Categories of Hemostatic Disorders

(1) Bleeding disorders

Platelet Disorders (Quantitative and Qualitative)
Coagulation Factor Deficiencies (Congenital and Acquired)

(2) Thrombosis – Congenital and Acquired

Platelet Disorders

clinical presentation bleeding (because platelets are involved in primary hemostasis)

Petichiae: Epitaxis (nose-bleed), Menorrhegia (vaginal bleeding), Hematuria (blood in urine)

(1) Qualitative – platelet function is abnormal

Mostly acquired (aspirin, or after being on heart/lung machine)
Prolonged bleeding time

Congenital Qualitative (rare)

Bernard-Soulier Syndrome- defects of membrane glycoproteins Ib

Glanzmann’s Thrombasthenia- defects in IIb/IIIa

Storage pool effect- defect in secretion stage

Acquired Qualitative – (common)

Drugs – Aspirin, NSAIDs
Uremia
Paraproteinemia – abnormal Immunoglobulins cover platelets and impair their functioning

(2) Quantitative Defect – Thrombocytopenia (ß platelet #)

Impaired production- bone marrow failure, Aplastic anemia, Leukemia

Increased destruction- either Auto-immune (Ab’s against glycoproteins on platelets) or Drug-induced

Increased Consumption- DIC (disseminated intravascular coagulation) and TPP (Thrombotic Thrombocytopenia Purpura)

Increased Sequestration- Splenomegaly

Thrombocytopenia - normal platelet count is 150-400 x 10⁹ /L

> 100 K = no risk of bleeding
50-75 K = risk of bleeding with major surgery or trauma
25-50 K = risk of bleeding with minor surgery or trauma
< 10 K = spontaneous bleeds (especially in CNS)

Immune (Auto/Allo) Thrombocytopenia

Formation of Ab’s (IgG, IgM, or IgA) against GP IIb/IIIa on platelets. Platelets get removed by macrophages in the spleen and liver
Treatment: Immunosuppresion

Drug-Induced Thrombocytopenia

Drug in combination with platelet looks appetizing to macrophages

DIC – widespread activation of coagulation

Infection – Gram neg septicemia

Cancer – procoagulant TF (tissue factor)

Major Trauma – tissue damage releases TF

Obstetrics – amniotic fluid embolism, septic abortion, retained dead fetus (releases TF)

Fibrin – platelet microthrombi in small vessels

Lab findings in DIC – prolonged PT (extrinsic) and APTT (intrinsic), ß platelets and fibrinogen, Ý D-dimers (this is diagnostic for DIC), fragmented RBC’s

Bleeding in DIC – cuts ooze

Consumption of coagulation factors and platelets
Heightened fibrinolysis
Circulating soluble fibrin/FSP (inhibits platelet function)

Management of DIC – most important to treat primary cause

Transfusion of platelets and/or FFP (Cryoprecipitate only if bleeding is severe/ like adding fuel to the fire)

TTP – vWF abnormality causes TTP

Microangiopathic Hemolytic anemia- Schistocytes (fragments of RBC’s) and Ý LDH

Thrombocytopenia

Neurological symptoms, renal involvement, and fever

pathology involves von Willabrand factor (vWF) – Large molecular weight glycoprotein, series of multimers in plasma, 500-20,000 kD

synthesized in Megakaryocytes and endothelium
causes platelet aggregation, binds to GP IIb/IIIa
vWF proteinase cleaves ultra large multimers of vWF to form heavy, intermediate, and small multimers
with TTP, too many Ultra Large Multimers (ULM) clog up small blood vessels

it is possible to differentiate between DIC and TTP by staining DIC = fibrin, TTP = vWF and Platelets

Management of TTP plasma exchange with FFP

Coagulation and Liver Disease

The liver is the site of synthesis of clotting factors and natural anticoagulants as well as the site of removal of complexes and activated factors.

Coagulation in the context of liver disease:

Ý PT, ß [II], [VII], and [IX] (decreased synthesis of the vitamin K factors)

dysfibrinogenia Ý sialic acid

t-PA increased Ý fibrinolysis

circulating activated factors (since the liver can not remove them) Þ DIC

DIC in Chronic Liver Disease:

low grade
decreased synthesis of natural anticoagulants, impaired clearance of activated factors
necrotic hepatocytes release TF
splenomegaly
can not remove endotoxins from the gut

Management if bleeding: give FFP

Congenital Bleeding Disorders

Prolonged PPT

due to VIII = Hemophilia A
due to IX = Hemophilia B (Amish)
due to XI = Uncommon (Ashkenazy Jews)
due to XII = no bleeding tendency

von Willebrand Disease

most common bleeding disorder, 1-2 % incidence of the general population

Hemophilia A – 2^nd most common disorder, X-linked (only affects males) usually presents in childhood

<1% of normal VIII = spontaneous bleeds, Hemathrosis (painfully swollen joints)
1-5% = occasional Hemathrosis, severe bleeding following surgery/trauma
5-20% = excessive bleeding after minor surgery/trauma
20-40% = excessive bleeding after major surgery/trauma

management of Hemophilia A – give concentrated VIII, recombinant VIII, monoclonal VIII, or Cryoprecipitate

Thrombotic Disorders

(1) Congenital Thrombophilia

Deficiencies of natural anti-coagulants

Anti-thrombin

Protein C

Protein S

Activated Protein C resistance

Incidence 25-50% of Pt’s with DVT (Deep Vein Thrombosis)
1-2% gene frequency

Anti-thrombin deficiency

normal thrombin level if 80-120%, <70% means Ý risk of DVT

anti-thrombin neutralizes thrombin and Xa, without it there is continued thrombin generation Þ continued clotting

2-3% incidence

heparin SO₄ and Dermatin SO₄ are the real activators of Anti-thrombin (AT)

Protein C and S deficiencies

vitamin K dependent natural anti-coagulants

inactivate activated Va and VIIIa

incidences : PS = 5% PC = 2-3%

heterozygous = mild to moderate // homozygous = serious Neonatal Purpura Fulimance – extensive skin necrosis due to microthrombi in skin blood vessels.

* Vitamin K deficiency has a greater effect on bleeding than on thrombosis

Protein S increases the conversion of Protein C to Activated Protein C (APC). APC then inactivates Va and VIIIa. With both deficienciesÞ more Va and VIIIa Þ thrombosis

Activated Protein C Resistance

Most common, 25-50% of DVT’s

Defect in Va degradation by APC = persistence of Va Þ increased [Va] in circulation

Heterozygous = 3-6 fold Ý risk // Homozygous = 20-40 fold Ý risk

2^nd hit; surgery, oral contraceptives, pregnancy, and Lupus anticoagulant also Ý risk

(2) Acquired Thrombophilia

Anti-phospholipid Antibody Syndrome

most common acquired thrombotic disorder
auto-antibodies against phospholipid

Anti-cardiolipin Ab - IgG, IgM, or IgA

Lupus anticoagulant Ab – IgG

Associated with various clinical manifestations due to thrombosis of arterial of venous side.

Lupus Anti-coagulant – causes thrombosis

Prolongs PPT by neutralizing the phospholipid involved in the in vitro test.

Clinical features: DVT, Pulmonary embolism, recurrent miscarriages, retinal vein thrombosis.

Lupus anticoagulant has antibodies that interfere with the conversion of Protein C Þ Activated Protein C

Treatment: use Heparin to keep patient’s PPT 1.5 – 2.5 x’s of normal

PPT Mixing Study for Inhibitor

Is prolonged PPT due to an inhibitor or ß factor?

To tell, mix with NPP (Normal Pooled Plasma)

Using NPP + Saline (in a one to one mix) as a reference, if NPP + patient’s plasma = 50% normal (that is equal to the reference) then it is due to ß factors

If the NPP + Pt’s plasma < 50% (less than the reference) then it is due to an inhibitor.

Blood Products