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  Topic: Blood-clotting, evolution, and Behe, References, links, and material on above< Next Oldest | Next Newest >  

Posts: 319
Joined: May 2002

(Permalink) Posted: May 24 2002,20:25   

Some more stuff I've gathered on the mysterious missing Hagemann factor case:

1) I went and re-checked Darwin's Black Box and Behe does indeed include the component as part of the IC blood-clotting system.***

2) Here is the abstract of the Robinson et al. paper that Wes cited:


Robinson, A. Jean, Kropatkin, Mona, and Aggeler, Paul M.  1969.   Hageman Factor (Factor XII) Deficiency in Marine Mammals. Science 166:1420-1422.

Hematologic and coagulation studies were conducted on Atlantic bottlenose dolphins and killer whales. Hematologic values were similar to those in man. These animals differed from other mammals in that the Hageman factor (factor XII) was absent and this absence caused marked prolongation of coagulation. Levels of VIII and V were high and those of VII and X were low compared with levels in man.

The paper mentions at the end a longish list of birds, reptiles, etc. that don't have Hagemann factor either, surprise suprise, although it mentions that at least some of these have other factors that may compensate...

Also of interest are the names of the orcas: "Orky" "Snorky" "Corky". Don't see those names as headers in scientific tables every day...

3) The conclusions of the Robinson et al. (1969) paper are backed up by this recent paper:


Pubmend citation

Thromb Res 1998 Apr 1;90(1):31-7

Whale Hageman factor (factor XII): prevented production due to pseudogene conversion.

Semba U, Shibuya Y, Okabe H, Yamamoto T.

In Southern blot analysis of the Hind III-digested whale genomic DNA obtained from the livers of two individual whales, we detected a single band with a size of five kilobase pairs which hybridized to full length guinea pig Hageman factor cDNA. We amplified two successive segments of the whale Hageman factor gene by polymerase chain reaction (PCR), and sequenced the PCR products with a combined total of 1367 base pairs. Although all of the exon-intron assemblies predicted were identical to those of the human Hageman factor gene, there were two nonsense mutations making stop codons and a single nucleotide insertion causing a reading frame shift. We could not detect any message of the Hageman factor gene expression by northern blot analysis or by reverse transcription-polymerase chain reaction (RT-PCR) analysis. These results suggest that in the whale, production of the Hageman factor protein is prevented due to conversion of its gene to a pseudogene. The deduced amino acid sequence of whale Hageman factor showed the highest homology with the bovine molecule among the land mammals analyzed so far.

In other words, this is a classic textbook-style case of pseudogene production, as well as being yet another bit of evidence supporting the whale-artiodactyl connection that has been suggested by various molecular studies and supported by recently discovered transitional fossils, see J. G. M. Thewissen's whale evolution page here.

4) It should be pointed out that while Behe includes Hageman factor (= Factor XII) as part of the IC blood-clotting system in DBB, the likely ID defense will be to take the "eternally receding IC system" approach wherein they declare this part non-essential and therefore not "part" of the IC "system" (if it's not part of the system, what it is a part of?).  

According to this t.o. POTM, it is indeed questionable how necessary Factor XII is for blood-clotting:


In this view, 3 factors included in the older scheme
(Factor XII = Hageman, prekallikrein and HMK) are now excluded, since deficiencies do not cause clinical disease, although they are associated with long clotting times in vitro. The role of XI isn't clear, since deficieny isn't invariably associated with disease.

...although one wonders if "deficiencies" means "complete absense", as it is apparent that Factor XII does play some important roles, e.g. the introduction to Semba et al. (1998) states:


Hageman factor (factor XII) is an initiation factor of plasma protease cascades, such as the intrinsic blood coagulation pathway and the plasma kinin system [1 and 2]. Important roles of the plasma kinin system in inflammatory responses in infection have been demonstrated. Microbial proteases such as Pseudomonas aeruginosa elastase, and negatively charged bacterial components such as endotoxin are capable of activating Hageman factor and prekallikrein [3, 4, 5 and 6].

...sounds like a handy thing to have around for sure.  Certainly on the above quote we can say that Hageman factor is necessary for "Hageman factor-dependent cascade activation", which just goes to show that just about anything can be considered "essential for function" depending on where one draws the lines of the "system".  

An even better feature of Semba et al. (1998) is that they propose a hypothesis for why Hagemann factor has been lost in marine mammals:


Saito et al. reported that all marine mammals examined by them did not possess coagulation activities equivalent to Hageman factor and prekallikrein [8]. Their explanation of this observation is as follows: the lack of these initiation factors of the intrinsic blood coagulation pathway must be advantageous to the marine mammals in prevention of disseminated intravascular coagulation syndrome which might occur in the semi-static state of blood circulation in the skin and the lungs under high hydrostatic pressure.


3. Discussion
The present study demonstrates that the Hageman factor gene converted to a pseudogene by the point mutations in exons coding for the protease domain in the whale. This conversion explains the absence of Hageman factor in whale plasma [8]. Messenger RNA of whale Hageman factor was not also detected in the liver mRNA fraction even by Southern blot analysis of the RT-PCR products. This result suggests very high instability of whale Hageman factor mRNA. Since only the 3' half of the whale Hageman factor gene has been analyzed so far, final conclusions about the mechanism of the blocked expression of the whale Hageman factor gene message cannot yet be drawn.

Participation of the intrinsic blood coagulation pathway in the disseminated intravascular coagulation syndrome has been suspected. The whale may dive to depths of 1000 m, where a semi-static state of blood circulation in the skin and the lungs might occur due to the high hydrostatic pressure. The fact that the initiation factor of the intrinsic blood coagulation system is not produced in the whale would support the clinical suspicion about the participation of this system in the disseminated intravascular coagulation syndrome.

We have been postulating that Hageman factor and the plasma kinin system play important roles in the host defense of land mammals. However, our hypothesis does not explain why Hageman factor-deficient individuals are not suffering from infectious deseases. Therefore, there may be an opposite hypothesis: the plasma kinin system does not play an essential role in host defense. From a superficial point of view, the present study might support this opposite hypothesis. However, Saito et al. reported that a significant amount of high-molecular weight kininogen was present in whale plasma [8]. This concentration corresponds to 30% of that in human plasma. We presently confirmed this using dolphin plasma (data not shown). If we take into account that the significant amount of high-molecular weight kininogen is present even in whale plasma, we could speculate that the important roles of the plasma kinin system are compensated by an unknown system(s) in Hageman factor-deficient individuals as well as in the marine mammals.

The deduced amino acid sequence of whale Hageman factor closely resembles that of the bovine molecule including the Pro-rich region where almost no homology is observed among the human, guinea pig, and bovine molecules [16]. Recently, Shimamura et al. [19] described their opinion that whales (including dolphins and porpoises), ruminants (cows, chevrotains, deer, sheep), and hippopotamuses form a monophyletic group. This is based on their analyses of two retroposons in the genomes of 15 mammalian species. Our present data support their opinion.

So, we appear to have parts being lost, perhaps "parts" being replaced or compensated for, and generally a lot of evolution going on.  One wonders how any of this would be explained on a "IDdidit" just-so story.


PS: Looking up 'related articles' in Pubmed reveals that decreased Factor XII activity is associated with increased miscarriage in humans:


PubMed link

Fertil Steril 2002 Feb;77(2):353-6

Coagulation factor XII activity, but not an associated common genetic polymorphism (46C/T),is linked to recurrent miscarriage.

Iinuma Y, Sugiura-Ogasawara M, Makino A, Ozaki Y, Suzumori N, Suzumori K.

Department of Obstetrics and Gynecology, Nagoya City University Medical School, Mizuho-ku, Nagoya 467-8601, Japan.

OBJECTIVE: To investigate whether a factor XII genetic polymorphism is associated with first-trimester embryonal loss. DESIGN: Prospective case-control study. SETTING; Nagoya City University Hospital. PATIENT(S): Eighty-three patients with a history of two or more unexplained first-trimester recurrent miscarriages and 67 controls with no obstetric complications or history of miscarriage. MAIN OUTCOME MEASURE(S): Plasma factor XII activity, a genetic polymorphism (46 C-->T) of factor XII, lupus anticoagulant, and beta(2)glycoprotein I dependent anticardiolipin antibodies. RESULT(S): Ten of the 83 patients and 1 of the 67 controls had decreased factor XII activity; the difference in frequency was statistically significant. Wild-type (CC), heterozygote (CT), and homozygote (TT) allele patterns were observed in 8, 36, and 39 patients, respectively, compared with 11, 20, and 36 of the patients and controls, respectively. The mean (+/- SD) corresponding factor XII activity was 154.8 +/- 44.8%, 112.7 +/- 30.2%, and 66.2 +/- 29.2% in patients and 164.6 +/- 26.7%, 114.3 +/- 28.1%, and 70.4 +/- 18.1% in controls. The two groups did not differ in the frequency of the T allele or categories of factor XII activity. CONCLUSION(S): Factor XII activity overall, but not the 46C/T common genetic polymorphism, is associated with recurrent miscarriage.
(bold added)

...which sure seems to imply that it is important for something.

Further support:


Pubmed link

Fertil Steril 2001 May;75(5):916-9

Factor XII but not protein C, protein S, antithrombin III, or factor XIII is a predictor of recurrent miscarriage.

Ogasawara MS, Aoki K, Katano K, Ozaki Y, Suzumori K.

Department of Obstetrics and Gynecology, Nagoya City University Medical School, Nagoya, Japan.

OBJECTIVE: To investigate whether a decrease in the values of protein C (PC), protein S (PS), antithrombin III (ATIII), factor XII (FXII), or factor XIII (FXIII) has predictive value for subsequent miscarriages. DESIGN: Prospective study. SETTING: Nagoya City University Medical School. PATIENT(S): A total of 536 patients with a history of two or more first-trimester miscarriages. INTERVENTION(S): One hundred and twelve patients treated with low-dose aspirin were excluded from the analysis. MAIN OUTCOME MEASURE(S): The subsequent pregnancy outcome of 424 patients was compared for abnormal and normal levels of each parameter. RESULT(S): There were no differences in the subsequent miscarriage rates between abnormal and normal values of PC, PS, ATIII, and FXIII. However, the rate with abnormal FXII is significantly higher than that with normal FXII. CONCLUSION(S): A decrease in FXII (but not in PC, PS, ATIII, or FXIII) predicts subsequent miscarriage in patients with a history of first-trimester recurrent miscarriages.

Here is another example of why missing Factor XII is not a good thing:


Ann Thorac Surg 2002 Jan;73(1):286-8

Huge left atrial thrombus with mitral stenosis in congenital factor XII deficiency.

Hasegawa T, Uematsu M, Tsukube T, Takemura Y, Okita Y.

Department of Surgery, Division II, Kobe University School of Medicine, Japan.

Factor XII deficiency has been reported to be a risk factor for thromboembolism as a result of inactivation of fibrinolysis. We describe a case of a huge left atrial thrombus with mitral stenosis, which was successfully removed surgically in a Factor XII deficient patient.

pubmed link

...and yet the ancestors of whales clearly had Hageman Factor, but lost it.  How is this possible unless Behe's argument about IC is fundamentally flawed?


*** Added in edit, Dec. 2002:

Actually, Behe did not.  It looks like it is on pp. 82 and 84, but on p. 86 Behe limits the system to only four components.  This was pointed out to me by DNAunion here:

On p. 86, Behe writes,


”Leaving aside the system before the fork in the pathway, where some details are less well known, the blood-clotting system first the definition of irreducible complexity. … The components of the system (beyond the fork in the road) are fibrinogen, prothrombin, Stuart factor, and proaccelerin. Just as none of the parts of the Foghorn [Leghorn] system is used for anything except controlling the fall of the telephone pole, so none of the cascade proteins are used for anything except controlling the formation of a blood clot. Yet in the absence of any one of the components, blood does not clot, and the system fails.” (Michael Behe, Darwin’s Black Box: The Biochemical Challenge to Evolution, Free Press, 1996, p86)

(copying from DNAunion)

Ken Miller, here,



Consider, for example, the intricate cascade of proteins involved in the clotting of vertebrate blood. This has been cited as one of the principal examples of the kind of complexity that evolution cannot generate, despite the elegant work of Russell Doolittle (Doolittle and Feng 1987; Doolittle 1993) to the contrary. A number of proteins are involved in this complex pathway, as described by Behe:

When an animal is cut, a protein called Hagemann factor (XII) sticks to the surface of cells near the wound. Bound Hagemann factor is then cleaved by a protein called HMK to yield activated Hagemann factor. Immediately the activated Hagemann factor converts another protein, called prekallikrein, to its active form, kallikrein. (Behe 1996a, 84)

How important are each of these proteins? In line with the dogma of irreducible complexity, Behe argues that each and every component must be in place before the system will work, and he is perfectly clear on this point:

. . . none of the cascade proteins are used for anything except controlling the formation of a clot. Yet in the absence of any of the components, blood does not clot, and the system fails. (Behe 1996a, 86)

As we have seen, the claim that every one of the components must be present for clotting to work is central to the "evidence" for design. One of those components, as these quotations indicate, is Factor XII, which initiates the cascade. Once again, however, a nasty little fact gets in the way of intelligent design theory. Dolphins lack Factor XII (Robinson, Kasting, and Aggeler 1969), and yet their blood clots perfectly well. How can this be if the clotting cascade is indeed irreducibly complex? It cannot, of course, and therefore the claim of irreducible complexity is wrong for this system as well. I would suggest, therefore, that the real reason for the rejection of "design" by the scientific community is remarkably simple – the claims of the intelligent design movement are contradicted time and time again by the scientific evidence.

...the second quote is pretty clearly out-of-context and Miller should have noted that Behe left himself some wiggle room in DBB concerning everything "before the fork" -- most of the cascade.  Behe only explicitly includes four parts in the IC system.

Edited by niiicholas on Dec. 07 2002,23:41

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