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CHAPTER 33: HEMOPHILIA AND OTHER INTRINSIC PATHWAY DEFECTS

INTRODUCTION

CASE HISTORY • Part 1

A 66-year-old man presents with a complaint of bruising and severe pain in the right arm and forearm after painting a wall yesterday. His history is notable for osteoarthritis, hypertension, and non–insulin-dependent diabetes mellitus; he denies any prior history of bleeding. His medications include hydrochlorothiazide and glyburide (a sulfonylurea), and he took ibuprofen for the pain last night. Examination is notable for large ecchymoses over the right shoulder and triceps, with swelling and tenderness of the right forearm and wrist. The remainder of the examination is benign.

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CBC: Hemoglobin/hematocrit - 13 g/dL/39%

MCV - 94 fL  MCH - 29 pg  MCHC - 28 g/dL

RDW-CV - 11%  WBC count - 13,500/μL
Differential:

Neutrophils - 45%

Lymphocytes - 50%

Monocytes - 5%
Platelet count - 300,000/μL

PT = 12.1 seconds (<14 seconds)

INR = 1.0 (<1.3)

PTT = 77 seconds (22–35 seconds)
Questions

  • Do the CBC and screening coagulation test results point to a specific cause for a bleeding tendency in this patient?

  • Are additional studies warranted for diagnosis or determining therapy?

Defects in the intrinsic pathway coagulation factors (factors VIII, IX, and XI) are associated with a significant bleeding tendency. The X-linked recessive disorders, hemophilia A (factor VIII) and B (factor IX), are the principal examples of this type of abnormality. A marked reduction in either factor VIII or IX is associated with spontaneous and excessive hemorrhage, especially hemarthroses and muscle hematomas. A deficiency in factor XI, which is encoded by a gene on chromosome 4, generally results in a less severe, but still significant, bleeding tendency.

THE NORMAL INTRINSIC PATHWAY

Laboratory-based interactions of the coagulation factors of the intrinsic pathway are illustrated in Figure 33-1. The initial activation stimulus is surface contact activation of factor XII (Hageman factor) to produce XIIa. This reaction is facilitated by the presence of high-molecular-weight kininogen (HMWK) and the conversion of prekallikrein (PK) to the active protease, kallikrein. Although this contact activation step is required in the measurement of the partial thromboplastin time (PTT), deficiencies of factor XII, HMWK, and PK are not associated with clinical bleeding.

FIGURE 33-1

The intrinsic pathway. The intrinsic pathway as measured by the PTT assay is initiated by surface contact (CS) (often via kaolin) with facilitation by high-molecular-weight kininogen (HMWK) and its conversion of prekallikrein to the active protease, kallikrein. This stimulus converts factor XII to XIIa, which in turn activates factor XI to XIa and factor IX to IXa. Factor IXa then catalyzes cleavage of factor X. In normal physiologic clotting, the Xase reaction is facilitated by binding of factor X to the activated platelet surface together with the critical cofactor VIIIa, which is generated in response to thrombin. Once Xa appears, there is further thrombin generation and formation of clot.

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