Disorders of Hemostasis

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 DDimers

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 supratherapeutic levels due to effects on the common pathway

History and Physical

Platelet Disorders
More common in Women Petechiae, Purpura, mucosal bleeding

Coagulation Disorder
More common in Men
Delayed deep muscle bleeding, hemarthrosis, hematuria More commonly congenital

More commonly acquired

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