Disorders of Hemostasis

Dr. Batizy

11/2/06

Primary Hemostasis

• The platelet contains lysosomes, granules, and trilaminar plasma membrane, microtubules.

• Granules are key in primary hemostasis and contain ADP, Thromboxane, platelet factor 4, adhesive and aggregation glycoproteins, coagulation factors, and fibrinolytic inhibitors

Primary Hemostasis

• Dependent on Platelets and Von Willebrand Factor (vWF)

• Platelets gather and attach to vWF

• Platelets degranulate after attachment and release ADP and Thromboxane which attracts more platelets

• Forms a platelet plug

• Requires endothelial damage to adhere

Secondary Hemostasis

• Platelet aggregation initiates secondary hemostasis through the coagulation cascade

• Coagulation cascade is initiated by the intrinsic or extrinsic pathway

• The final cascade results in fibrin deposition cross-linking platelets and clot formation

The Coagulation Cascade

Common Pathway

A word on clotting factors

• Vitamin K Dependent Factors– Intrinsic Pathway : IX, X– Common Pathway: II– Extrinsic Pathway: VII

• All clotting Factors are produced in liver except vWF/VIII

• VIII produced by the vascular endothelium • Sites of heparin activity

– IIa, IXa, Xa ( major site), XIa, Platelet factor 3

A word on clotting factors

• Factor VIII – A factor by any other name?– Same factor: 3 different activities– VIII:C – antihemophilic or coagulation activity– vWF – supports platelet adhesion and carries

VIII in the blood– VIII:Ag – reacts with rabbit antibodies, relates

to measured plasma level rather than activity

Fibrinolysis

• The Ying to the Yang of clot formation

• Tissue Plasminogen activator (tPA) – Released from endothelial cells

• Converts plasminogen to plasmin which degrades fibrinogen and fibrin into fibrin degradation products

• Cross linked fibrin is cleaved into D-Dimers

Testing the hemostatic system

• CBC– H/H drops often lag behind actual RBC loss due to

slow equilibration

• Blood smear– Schistocytes and fragemented RBC- DIC– Teardrop-shaped or nucleated RBC – Myelophthisic

disease– Characteristic WBC morphologies seen in

thrombocytopenia in infectious mononucleosus, folate, B12 deficiency, or leukemia

Testing the hemostatic system

• Platelet count– Thrombocytopenia : Less that 100,000/mL– Spontaneous bleeding possible: Less than

20,000/mL– Count does not have anything to do with

functionality of platelet

Testing the hemostatic system

• Bleeding time– Tests vascular integrity and platelet function– Incision on volar aspect of the forearm 1mm

deep and 1 cm long– BP cuff inflated to 40 mmHg– Normal < 8 minutes– Borderline 8-10 minutes– Abnormal 10 + minutes– Affected by ASA (permanent) and NSAIDs

Testing the hemostatic system

• Bleeding time– Prolonged with platelet counts below 100,000– When prolonged with platelet count over

100,000 suggests platelet dysfunction

Testing the hemostatic system

• Prothrombin Time– Test of extrinsic and common pathways– International Normalized Ratio used to

compensate for differences in thromboplastin reagents

– Used for coumadin– Elevated in patients with liver disease and

abnormalities in vitamin K sensitive factors

Testing the hemostatic system

• Partial Thromboplastin Time (PTT)– Tests intrinsic and common pathway– Average normal 25-29– Factor levels usually less than 40% to be

affected– Affected by heparin– Can be effected by coumadin at supra-

therapeutic levels due to effects on the common pathway

History and Physical

• Platelet Disorders– More common in

Women– Petechiae, Purpura,

mucosal bleeding

– More commonly acquired

• Coagulation Disorder– More common in Men

– Delayed deep muscle bleeding, hemarthrosis, hematuria

– More commonly congenital

Thrombocytopenia

• Usually mucosal bleeding

• Epistaxis, menorrhagia, and GI bleeding is common

• Trauma does not usually cause bleeding

Thrombocytopenia

• Three mechanisms of Thrombocytopenia– Decreased production

• Usually chemotherapy, myelophthisic disease, or BM effects of alcohol or thiazides

– Splenic Sequesteration• Rare• Results from malignancy, portal hypertension, or

increased Splenic RBC destruction ( hereditary spherocytosis, autoimmune hemolytic anemia)

– Increased Destruction

Thrombocytopenia

• Immune thrombocytopenia– Multiple causes including drugs, lymphoma, leukemia,

collagen vascular disease– Drugs Include

• Digitoxin, sulfonamindes, phenytoin, heparin, ASA, cocaine, Quinine, quinidine, glycoprotein IIb-IIa antagonists

– After stopping drugs platelet counts usually improve over 3 to 7 days

– Prednisone (1mg/kg) with rapid taper can shorten course

Thrombocytopenia

• HIT– Important Immunologic Thrombocytopenia– Usually within 5-7 days of Initiation of Heparin

Therapy but late onset cases are 14-40 days– Occurrence 1-5% with unfractionated heparin

and less than 1% with low molecular-weight heparin

– Thrombotic complications in up to 50% of HIT with loss of limb in 20% and mortality up to 30%

ITP

• Diagnosis of exclusion

• Associated with IgG anti-platelet antibody

• Platelet count falls to less that 20,000

ITP

• Acute Form– Most common in children 2 to 6 years– Viral Prodrome common in the 3 weeks prior– Self Limited and > 90% remission rate– Supportive Treatment– Steroids are not helpful

ITP

• Chronic Form– Adult disease primarily– Women more often than men– Insidious onset with no prodrome– Symptoms include: easy bruising, prolonged

menses, mucosal bleeding– Bleeding complications are unpredictable– Mortality is 1%– Spontaneous remission is rare

ITP

• Chronic Form– Hospitalization common because of a

complex differential diagnosis– Multiple treatments– Platelet transfusions are used only for life

threatening bleeding– Life threatening bleeding is treated with IV

Immune globulin (1g/kg)

TTPHUS

• Exist on a continuum and are likely the same disease

• Diagnosed by a common pentad– Microangiopathic Hemolytic Anemia: Schistocytes

membranes are sheared passing through microthrombi

– Thrombocytopenia: More sever in TTP– Fever– Renal Abnormalities: More prominent in HUS: include

Renal insufficiency, azotemia, proteinuria, hematuria, and renal failure

– Neurologic Abnormalities: hallmark of TTP 1/3 of HUS: Sx of HA, confusion, CN palsies, seizure,coma

TTPHUS

• Labs– PT, PTT, and fibrinogen are within reference

range– Helmet Cells (Shistocytes) are common

TTPHUS

• HUS– Most common in infants and children 6mo - 4

years– Often associated with a prodromal diarrhea– Strongest association to E. coli O157:H7 but

also associated with SSYC as well as multiple virus

– Prognosis• Mortality 5-15%• Younger patients do better

TTPHUS

• HUS– Treatment

• Mostly supportive• Plasma exchange reserved for sever cases• Treat hyperkalemia• Avoid antibiotics with Ecoli

– May actually increase verotoxin production with TMP-SMX

– May be helpful with cases of Shigella dysenteriae

TTPHUS

• TTP– More common in adults– Untreated mortality rate of 80% 1 to 3 months

after diagnosis– Aggressive plasma exchange has dropped

the mortality to 17%– Splenectomy, immune globulin, vincristine all

play a role in therapy

TTPHUS

• AVOID PLATELET TRANSFUSION– May lead to additional microthrombi in

circulation– Transfuse only with life threatening bleeding

Dilutional Thrombocytopenia

• PRBC are platelet poor

• Monitor platelet count with every 10 u PRBC

• Transfuse when count below 50,000

• Get them upstairs before you transfuse 10 units PRBC

DIC

• A few harmless snowflakes working together can create an avalanche of Destruction.

DIC

• Early recognition important secondary to potentially devastating sequelae and effective therapy

• DIC Sequence Platelets and coagulation factors consumed Thrombin directly activates fibrinogen Fibrin deposition Fibrinolysis Inhibition of platelets and fibrin polymerization Decrease in inhibition levels

• Entire process leads to a massive consumption of coagulation factors

DIC

• Life threatening combination of bleeding diathesis with small vessel ischemia

• There are varying levels of acuity • Recommended testing

– Peripheral Smear: Low platelets, schistocytes– Platelet count: Low (<100,000)– Pt, PTT, Thrombin Time: Prolonged– Fibrinogen: Low– Fibrin degredation products: zero to large

DIC

• Treatment– Dependent on whether bleeding or ischemia

predominate– If bleeding

• Platelets, FFP or Cryoprecipitate, and blood recommended

– With Ischemia• Heparin has a place in treatment• Examples include Retained fetus, purpura

fulminans, giant hemangioma, and acute promyelocytic leukemia

DIC

• Treatment– Goal in ER is suspicion, aggressive pursuit of

diagnosis, understanding complications, and rarely initiation of therapy

Coagulation Pathway Defects

• Hemophilia A

• Von Willebrand’s Disease

• Hemophilia B ( Christmas Disease)

Hemophilia A

Hemophilia A

• Variant form of Factor VIII

• 60 to 80 persons per million

• 70% Sex linked recessive

• Severity linked to level of VIII:C activity– 1% Severe– 1%-5% Moderate– 5-10% mild ( little risk of spontaneous

bleeding)

Hemophilia A

• Bleeding can occur anywhere – Deep muscles – Joints– Urinary Tract– Intracranial

• Recurrent Hemarthrosis and progressive join destruction are major cause of morbidity

• Intracranial bleed is major cause of death in all hemophiliacs

Hemophilia A

• Mucosal bleeding is rare unless associated with von Willebrands or Platelet inhibition

• Unlike platelet defects Trauma initiates bleeding

• Bleeding can occur usually by 8 hours but as late as 1 to 3 days after trauma

Hemophilia A

• Management:– Home therapy is increasingly common and

most report to ER only with complicated problems or Trauma

– Hospitals should have files of known hemophiliacs in the area

– Accepted therapy is with Factor VIII replacement or VIII:C

– Newer preparation carry lower risk for Hep B and Hep C transmission

Hemophilia A

• Management:– Multiple guidelines for therapy institution– Most important physician should believe a

patient saying they are bleeding and institute early therapy

Hemophilia A

• Prophylaxis– May require admission for anticipation of

delayed bleeding– Candidates:

• Deep lacerations• Soft tissue injury where hematoma could be

destructive ie: eye, mouth, neck, back, and spinal column

Hemophilia A

• Treatment of haemophilic synovitis– COX-2 important in Hemophiliacs because of

anti=inflammatory,and analgesic properties but they do not affect the platelet fuction

– With withdrawl of rofecoxib from the market celecoxib had become popular

– Study has shown that Celecoxib gives good relief of synovitis without serious adverse effects

Von Willebrand’s Disease

• Most common inherited bleeding disorder

• Without vWF the ability of platelets to adhere is diminished

• VIII:C has diminished activity

• Bleeding sites are primarily mucosal

• Hemarthrosis is rare

• Menorrhagia and GI bleed are common

Von Willebrand’s Disease

• Factor VIII replacement is treatment of choice

• FFP may be given in extreme circumstances

• Desmopressin is only useful for specific types of vWD and should only be give with advice from hematologist

Hemophilia B (Christmas Disease)

Hemophilia B (Christmas Disease)

• Clinically indistinguishable from hemophilia A

• Deficiency of factor IX

• Factor IX preparation used in treatment

• FFP and plasma prothrombin complex are also useful

• Gene manipulation in animals shows promising results for the future

Take home message

• All Bleeding stops…. Eventually

References

• Rosen’s

• Emedicine

• Celecoxib in the treatment of haemophilic synovitis, target joints, and pain in adults and children with haemophilia, Haemophilia (2006), 12, 514-517