# Presentation: 461281

## Bleeding Disorders

**Bleeding Disorders**

- Morey A. Blinder, M.D.
*Associate Professor of Medicine*
*and Pathology & Immunology*

## Objectives

**Objectives**

- Coagulation factor disorders and treatment
- Disorders of platelets and platelet transfusion
- Adjunctive drug therapy for bleeding

## Coagulation factor disorders requiring blood products

## Coagulation factor disorders

- Inherited bleeding disorders
- Hemophilia A and B
- vonWillebrands disease
- Other factor deficiencies

- Acquired bleeding disorders
- Liver disease
- Vitamin K deficiency/warfarin overdose
- DIC

## Ecchymoses

- (typical of coagulation factor disorders)

## Hemophilia A and B

**	**				**Hemophilia A****	****	****Hemophilia B**
- Coagulation factor deficiency		Factor VIII		Factor IX
-                              Inheritance		X-linked			X-linked
- 					recessive 		recessive
-                                Incidence		1/10,000 males		1/50,000 males
-                                  Severity			Related to factor level
- 					<1% - Severe - spontaneous bleeding
- 					1-5% - Moderate - bleeding with mild injury
- 					5-25% - Mild - bleeding with surgery or trauma
-                         Complications			Soft tissue bleeding

## Hemophilia

- Clinical manifestations (hemophilia A & B indistinguishable)
- Hemarthrosis (most common)
- Fixed joints
- Soft tissue hematomas (e.g., muscle)
- Muscle atrophy
- Shortened tendons
- Other sites of bleeding
- Urinary tract
- CNS, neck (may be life-threatening)
- Prolonged bleeding after surgery or dental extractions

## Treatment of hemophilia A

- Intermediate purity plasma products
- Virucidally treated
- May contain von Willebrand factor
- High purity (monoclonal) plasma products
- Virucidally treated
- No functional von Willebrand factor
- Recombinant factor VIII
- Virus free/No apparent risk
- No functional von Willebrand factor

## Factor VIII Infusion

**Factor VIII Infusion**

## Dosing guidelines for hemophilia A

- Mild bleeding
- Target: 30% dosing q8-12h; 1-2 days (15U/kg)
- Hemarthrosis, oropharyngeal or dental, epistaxis, hematuria
- Major bleeding
- Target: 80-100% q8-12h; 7-14 days (50U/kg)
- CNS trauma, hemorrhage, lumbar puncture
- Surgery
- Retroperitoneal hemorrhage
- GI bleeding
- Adjunctive therapy
-  amino caproic acid (Amicar) or DDAVP (for mild disease only)

## Complications of therapy

- Formation of inhibitors (antibodies)
- 10-15% of severe hemophilia A patients
- 1-2% of severe hemophilia B patients
- Viral infections
- Hepatitis B			Human parvovirus
- Hepatitis C			Hepatitis A
- HIV				Other

## Treatment of hemophilia B

- Agent
- High purity factor IX
- Recombinant human factor IX
- Dose
- Initial dose: 100U/kg
- Subsequent: 50 U/kg every 24 hours

## von Willebrand DiseaseClinical features

- von Willebrand factor	Carrier of factor VIII								Anchors platelets to subendothelium						Bridge between platelets
- Inheritance			Autosomal dominant
- Incidence 			1/10,000
- Clinical features		Mucocutaneous bleeding

## Laboratory evaluation of von Willebrand disease

- 	Classification
- Type 1 		Partial quantitative deficiency
- Type 2 		Qualitative deficiency
- Type 3		Total quantitative deficiency
- Diagnostic tests:

## Treatment of von Willebrand diseaseVaries by Classification

- Cryoprecipitate
- Source of fibrinogen, factor VIII and VWF
- Only plasma fraction that consistently contains VWF multimers
- Correction of bleeding time is variable
- DDAVP (Deamino-8-arginine vasopressin)
- Increases plasma VWF levels by stimulating secretion from endothelium
- Duration of response is variable
- Used for type 1 disease
- Dosage 0.3 μg/kg q 12 hr IV
- Factor VIII concentrate (Humate-P)
- Virally inactivated product
- Used for type 2 and 3

## Vitamin K deficiency

- Source of vitamin K 		Green vegetables								Synthesized by intestinal flora
- Required for synthesis		Factors II, VII, IX ,X								Protein C and S
- Causes of deficiency		Malnutrition									Biliary obstruction								Malabsorption								Antibiotic therapy
- Treatment				Vitamin K									Fresh frozen plasma

## Vitamin K deficiency due to warfarin overdoseManaging high INR values

- Clinical situation	Guidelines
- INR therapeutic-5	Lower or omit next dose;
- 			Resume therapy when INR is therapeutic
- INR 5-9; no bleeding	Lower or omit next dose;
- 			Resume therapy when INR is therapeutic
- 			Omit dose and give vitamin K (1-2.5mg po)
- 			Rapid reversal: vitamin K 2-4 mg po (repeat)
- INR >9; no bleeding	Omit dose; vitamin K 3-5 mg po; repeat as necessary
- 			Resume therapy at lower dose when INR therapeutic

*Chest 2001:119;22-38s (supplement) *

## Vitamin K deficiency due to warfarin overdoseManaging high INR values in bleeding patients

- Clinical situation		Guidelines
- INR > 20; serious bleeding	Omit warfarin
- Any life-threatening bleeding	Vitamin K 10 mg slow IV infusion
- 				FFP ± factor rhVIIa (depending on urgency)
- 				Repeat vitamin K injections every 12 hrs as needed

## Disseminated Intravascular Coagulation (DIC)Mechanism

**Systemic activation**
**of coagulation**

**Intravascular**
**deposition of fibrin**

**Depletion of platelets**
**and coagulation factors**

**Bleeding**

**Thrombosis of small**
**and midsize vessels**
**with organ failure**

## Common clinical conditionsassociated with DIC

- Sepsis
- Trauma
- Head injury
- Fat embolism
- Malignancy
- Obstetrical complications
- Amniotic fluid embolism
- Abruptio placentae

- Vascular disorders
- Reaction to toxin (e.g. snake venom, drugs)
- Immunologic disorders
- Severe allergic reaction
- Transplant rejection

## DICTreatment approaches

- Treatment of underlying disorder
- Anticoagulation with heparin
- Platelet transfusion
- Fresh frozen plasma

## Liver Disease

- Decreased synthesis of II, VII, IX, X, XI, and fibrinogen
- Prolongation of PT, aPTT and Thrombin Time
- Often complicated by
- Gastritis, esophageal varices, DIC
- Treatment
- Fresh-frozen plasma infusion (immediate but temporary effect)
- Vitamin K (usually ineffective)

## Coagulation cascade

**Coagulation cascade**

**Vitamin K dependant factors**

**XIIa**

**IIa**

**Intrinsic system **(surface contact)

**XII**

**XI**

**XIa**

**Tissue factor**

**IX**

**IXa**

**VIIa**

**VII**

**VIII**

**VIIIa**

**Extrinsic system **(tissue damage)

**X**

**V**

**Va**

**II**

**Fibrinogen**

**Fibrin**

**(Thrombin)**

**IIa**

**Xa**

**Notes:**
	KEY POINT: The efficacy/safety ratio for currently available therapies is less than satisfactory due to their ill-defined, multitargeted activity. New antithrombotic strategies are needed that offer an improved efficacy/safety profile compared with existing antithrombotic agents.1,2 

Currently available antithrombotic agents include the heparins (UFH and Enoxaparin), vitamin K antagonists (warfarin), and direct thrombin inhibitors (hirudins).3–6
The most widely used agents, heparins and vitamin K antagonists, have a range of actions on various components of the coagulation cascade.  This contributes to the unpredictable clinical responses associated with these agents.3–5
Other limitations of currently available antithrombotics include3–7
  High incidence of serious adverse effects, particularly bleeding complications
  Routine monitoring of coagulation markers may be needed and represents a substantial 
	burden in terms of time and costs
  Narrow therapeutic margin 
  Limited effectiveness in preventing VTE
Factor Xa inhibitors are a novel class of antithrombotic agents designed to selectively target only 1 core step in the coagulation cascade, leading to potent and targeted effectiveness.8

## Laboratory Evaluation of the Coagulation Pathways

- Partial thromboplastin time
- (PTT)

- Prothrombin time
- (PT)

*Intrinsic pathway*

*Extrinsic pathway*

*Common pathway*

- Thrombin time

- Thrombin

- Surface activating agent
-    (Ellagic acid, kaolin)
- Phospholipid
- Calcium

- Thromboplastin
-    Tissue factor
-    Phospholipid
- Calcium

*Fibrin clot*

## Pre-analytic errors

***Problems with blue-top tube***
- Partial fill tubes
- Vacuum leak and citrate evaporation
***Problems with phlebotomy***
- Heparin contamination
- Wrong label
- Slow fill
- Underfill
- Vigorous shaking

***Biological effects***
- Hct ≥55 or ≤15
- Lipemia, hyperbilirubinemia, hemolysis
***Laboratory errors***
- Delay in testing
- Prolonged incubation at 37°C
- Freeze/thaw deterioration

## Initial Evaluation of a Bleeding Patient - 1

- Normal PT
- Normal PTT

- _Consider evaluating for:_
-    Mild factor deficiency 		Monoclonal gammopathy
-    Abnormal fibrinolysis		Platelet disorder
-        (2 anti-plasmin def)		Vascular disorder
-    Elevated FDPs

- Urea
- solubility

*Normal*

*Abnormal*

- Factor XIII
- deficiency

## Initial Evaluation of a Bleeding Patient - 2

**Initial Evaluation of a Bleeding Patient - 2**

- Normal PT
- Abnormal PTT

- Test for factor deficiency:
-     Isolated deficiency in intrinsic pathway (factors VIII, IX, XI)
-     Multiple factor deficiencies (rare)

- Repeat
- with
- 50:50
- mix

*50:50 mix is normal*

*50:50 mix is abnormal*

- Test for inhibitor activity:
-    Specific factors: VIII,IX, XI
-    Non-specific (anti-phospholipid Ab)

## Initial Evaluation of a Bleeding Patient - 3

**Initial Evaluation of a Bleeding Patient - 3**

- Abnormal PT
- Normal PTT

- Test for factor deficiency:
-     Isolated deficiency of factor VII (rare)
-     Multiple factor deficiencies (common)
-       *(Liver disease, vitamin K deficiency, warfarin, DIC)*

- Repeat
- with
- 50:50
- mix

*50:50 mix is normal*

*50:50 mix is abnormal*

- Test for inhibitor activity:
-    Specific:  Factor VII (rare)
-    Non-specific: Anti-phospholipid (rare)

## Initial Evaluation of a Bleeding Patient - 4

**Initial Evaluation of a Bleeding Patient - 4**

- Abnormal PT
- Abnormal PTT

- Test for factor deficiency:
-     Isolated deficiency in common pathway: Factors V, X,
-        Prothrombin, Fibrinogen
-     Multiple factor deficiencies (common)
-        *(Liver disease, vitamin K deficiency, warfarin, DIC)*

- Repeat
- with
- 50:50
- mix

*50:50 mix is normal*

*50:50 mix is abnormal*

- Test for inhibitor activity:
-    Specific : Factors V, X, Prothrombin,         	    fibrinogen (rare)
-    Non-specific: anti-phospholipid (common)

## Coagulation factor deficienciesSummary

- Sex-linked recessive
- 	 Factors VIII and IX deficiencies cause bleeding
- Prolonged PTT; PT normal
- Autosomal recessive (rare)
-  Factors II, V, VII, X, XI, fibrinogen deficiencies cause bleeding
- Prolonged PT and/or PTT
-  Factor XIII deficiency is associated with bleeding and
- 		impaired wound healing
- PT/ PTT normal; clot solubility abnormal
-  Factor XII, prekallikrein, HMWK deficiencies
- 		do not cause bleeding

## Disorders of Platelets and Platelet Transfusion

## Sites of bleeding in thrombocytopenia

- Skin and mucous membranes
- Petechiae
- Ecchymosis
- Hemorrhagic vesicles
- Gingival bleeding and epistaxis
- Menorrhagia
- Gastrointestinal bleeding
- Intracranial bleeding

## Petechiae

**Do not blanch with pressure****      (cf. angiomas)****Not palpable****      (cf. vasculitis)**

## Classification of platelet disorders

- Quantitative disorders
- Abnormal distribution
- Dilution effect
- Decreased production
- Increased destruction

- Qualitative disorders
- Inherited disorders (rare)
- Acquired disorders
- Medications
- Chronic renal failure
- Cardiopulmonary bypass

## Acquired thrombocytopenia with shortened platelet survival

- Associated with bleeding
- Immune-mediated thrombocytopenia (ITP)
- Most drug-induced thrombocytopenias
- Most others

-      Associated with                   	thrombosis
- Thrombotic thrombocytopenic purpura
- DIC
- Trousseau’s syndrome
- Heparin-associated thrombocytopenia

## Approach to the thrombocytopenic patient

- History
- Is the patient bleeding?
- Are there symptoms of a secondary illness? (neoplasm, infection, autoimmune disease)
- Is there a history of medications, alcohol use, or recent transfusion?
- Are there risk factors for HIV infection?
- Is there a family history of thrombocytopenia?
- Do the sites of bleeding suggest a platelet defect?
- Assess the number and function of platelets
- CBC with peripheral smear
- Platelet function study

## Platelet function screen

- Replaces the *bleeding time* as a test of platelet function
- PFA-100; ordered as “platelet function screen”
- Blue top tube
- Measures the time it takes for blood to block membrane coated with either collagen/epinephrine or collagen/ADP

## Platelet function screenResults

**Platelet function ****screen****Results**

- Epi		ADP			Interpretation
- Normal	Normal		Normal platelet function
- Abnormal	Normal		“Aspirin effect”
- Abnormal	Abnormal		Abnormal platelet function
- 					Valvular heart disease
- 					Renal failure
- 					Von Willebrand disease

## Platelet transfusions

- Source
- Platelet concentrate (Random donor)
- 	Each donor unit should increase platelet count ~10,000 /μl
- Pheresis platelets (Single donor)
- Storage
- Up to 5 days at room temperature
- “Platelet trigger”
- Bone marrow suppressed patient (>10-20,000/μl)
- Bleeding/surgical patient (>50,000/μl)

## Platelet transfusions - complications

- Transfusion reactions
- Higher incidence than in RBC transfusions
- Related to length of storage/leukocytes/RBC mismatch
- Bacterial contamination
- Platelet transfusion refractoriness
- Alloimmune destruction of platelets (HLA antigens)
- Non-immune refractoriness
- Microangiopathic hemolytic anemia
- Coagulopathy
- Splenic sequestration
- Fever and infection
- Medications (Amphotericin, vancomycin, ATG, Interferons)

## Laboratory Evaluation of BleedingOverview

- CBC and smear	Platelet count	Thrombocytopenia
- 	RBC and platelet morphology	TTP, DIC, etc.
- Coagulation	Prothrombin time	Extrinsic/common pathways
- 	Partial thromboplastin time	Intrinsic/common pathways
- 	Coagulation factor assays	Specific factor deficiencies
- 	50:50 mix	Inhibitors (e.g., antibodies)
- 	Fibrinogen assay	Decreased fibrinogen
- 	Thrombin time	Qualitative/quantitative
- 		      fibrinogen defects
- 	FDPs or D-dimer	Fibrinolysis (DIC)
- Platelet function	von Willebrand factor	vWD
- 	Bleeding time	*In vivo* test (non-specific)
- 	Platelet function analyzer (PFA)	Qualitative platelet disorders 			 and  vWD
- 	Platelet function tests	Qualitative platelet disorders

## Adjunctive therapy forbleeding disorders

- Adjunctive therapy forbleeding disorders

## Adjunctive drug therapy for bleeding

**Adjunctive drug therapy for bleeding**

- Fresh frozen plasma
- Cryoprecipitate
- Epsilon-amino-caproic acid (Amicar)
- DDAVP
- Recombinant human factor VIIa (Novoseven)

## Fresh frozen plasma

- Content - plasma (decreased factor V and VIII)
- Indications
- Multiple coagulation deficiencies (liver disease, trauma)
- DIC
- Warfarin reversal
- Coagulation deficiency (factor XI or VII)
- Dose (225 ml/unit)
- 10-15 ml/kg
- Note
- Viral screened product
- ABO compatible

## Cryoprecipitate

- Prepared from FFP
- Content
- Factor VIII, von Willebrand factor, fibrinogen
- Indications
- Fibrinogen deficiency
- Uremia
- von Willebrand disease
- Dose (1 unit = 1 bag)
- 1-2 units/10 kg body weight

## Aminocaproic acid (Amicar)

- Mechanism
- Prevent activation plaminogen -> plasmin
- Dose
- 50mg/kg po or IV q 4 hr
- Uses
- Primary menorrhagia
- Oral bleeding
- Bleeding in patients with thrombocytopenia
- Blood loss during cardiac surgery
- Side effects
- GI toxicity
- Thrombi formation

## Desmopressin (DDAVP)

- Mechanism
- Increased release of VWF from endothelium
- Dose
- 0.3μg/kg IV q12 hrs
- 150mg intranasal q12hrs
- Uses
- Most patients with von Willebrand disease
- Mild hemophilia A
- Side effects
- Facial flushing and headache
- Water retention and hyponatremia

## Recombinant human factor VIIa(rhVIIa; Novoseven)

- Mechanism
- Activates coagulation system through extrinsic pathway
- Approved Use
- Factor VIII inhibitors in hemophiliacs
- Dose: (1.2 mg/vial)
- 90 μg/kg q 2 hr
- “Adjust as clinically indicated”
- Cost (70 kg person) @  $1/μg
- ~$5,000/dose or $60,000/day

## Recombinant human factor VIIain non-approved settings

- Surgery or trauma with profuse bleeding
- Consider in patients with excessive bleeding without apparent surgical source and no response to other components
- Dose: 50-100ug/kg for 1-2 doses
- Risk of thrombotic complications not well defined
- Anticoagulation therapy with bleeding
- 20ug/kg with FFP if life or limb at risk; repeat if needed for bleeding

## Approach to bleeding: Summary

- Identify and correct any specific defect of hemostasis
- Use non-transfusional drugs whenever possible
- RBC transfusion for surgical procedures or large blood loss